Modulation of dysregulated cancer metabolism by plant secondary metabolites: A mechanistic review

Journal Pre-proof Modulation of dysregulated cancer metabolism by plant secondary metabolites: A mechanistic review Sajad Fakhri, Seyed Zachariah Moradi, Mohammad Hosein Farzaei, Anupam Bishayee

PII:

S1044-579X(20)30040-7

DOI:

https://doi.org/10.1016/j.semcancer.2020.02.007

Reference:

YSCBI 1774

To appear in:

Seminars in Cancer Biology

Received Date:

30 December 2019

Revised Date:

8 February 2020

Accepted Date:

10 February 2020

Please cite this article as: Fakhri S, Moradi SZ, Farzaei MH, Bishayee A, Modulation of dysregulated cancer metabolism by plant secondary metabolites: A mechanistic review, Seminars in Cancer Biology (2020), doi: https://doi.org/10.1016/j.semcancer.2020.02.007

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Modulation of dysregulated cancer metabolism by plant secondary metabolites: A mechanistic review

Sajad Fakhria, Seyed Zachariah Moradia,b, Mohammad Hosein Farzaeia,**, Anupam

Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical

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a

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Bishayeec,*

b

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Sciences, Kermanshah 6734667149, Iran

Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah

Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA

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6734667149, Iran

USA

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*Corresponding author at: Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211,

**Corresponding author at: Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran addresses:

[email protected]

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E-mail

[email protected] (M.H.F.)

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or

[email protected]

(A.B.);

Abstract Several signaling pathways and basic metabolites are responsible for the control of metabolism in both normal and cancer cells. As emerging hallmarks of cancer metabolism, the abnormal activities of these pathways are of the most noticeable events in cancer. This altered metabolism expedites the survival and proliferation of cancer cells, which have attracted a substantial amount

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of interest in cancer metabolism. Nowadays, targeting metabolism and cross-linked signaling pathways in cancer has been a hot topic to investigate novel drugs against cancer. Despite the

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efficiency of conventional drugs in cancer therapy, their associated toxicity, resistance, and high-

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cost cause limitations in their application. Besides, considering the numerous signaling pathways cross-linked with cancer metabolism, discovery, and development of multi-targeted and safe

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natural compounds is a high priority. Natural secondary metabolites have exhibited promising anticancer effects by targeting dysregulated signaling pathways linked to cancer metabolism. The

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present review reveals the metabolism and cross-linked dysregulated signaling pathways in cancer. The promising therapeutic targets in cancer, as well as the critical role of natural

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secondary metabolites for significant anticancer enhancements, have also been highlighted to find novel/potential therapeutic agents for cancer treatment.

Keywords:

Plant

secondary

metabolites,

Cancer

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Pharmacology, Therapeutic targets

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metabolism,

Signaling

pathways,

1.

Introduction Cancer metabolism is primarily an accelerated metabolism of glucose and glutamine [1]. As

emanated from the initial seminal observation of Otto Warburg, cancer cells have a higher ability in taking up glucose and producing lactate even in the presence of oxygen. This phenomenon called aerobic glycolysis or the Warburg effect which resulted in extracellular acidic fluid [2, 3]. Using fluorodeoxyglucose-positron emission tomography and magnetic resonance spectroscopy,

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as pioneering technologies, have allowed detecting a tumor tissue with a feature of high glucose

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avidity [4]. In addition to the critical role of glucose metabolism in the overproliferation of cancer cells, the contribution of other nutrients, including citrate, aspartate, glutamate, and

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lactate, is also revealed [5, 6]. In this line, citrate and aspartate generated from tricarboxylic acid

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(TCA) intermediates play key roles in lipid and protein synthesis, respectively. In the lack of TCA intermediates, glutamine would be a crucial contributor to the anaplerosis process to

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support ATP biosynthesis/generation in cancer cells [7-9]. Anaplerosis reactions are chemical reactions of forming intermediates of cancer metabolic pathways [10]. Hence, the scavenging of

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lipids as well as protein catabolism could also contribute carbon to the TCA cycle, thereby supporting the overproliferation of cancer cells [11, 12]. Accordingly, the metabolism of carbohydrate, protein, and lipid is considered as the main pathway possessing key roles in cancer metabolism.

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In addition to the critical role of glucose and aerobic glycolysis as well as glutamine and

citrate in cancer metabolism, several other signaling pathways, including inflammatory, oxidative, apoptotic, and autophagy, have also been well-known in cancer [13]. This is due to their near linkage with cancer metabolic pathways. Briefly, cancer-associated metabolic dysregulations are categorized into six hallmarks, namely dysregulated uptake of glucose and

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amino acids, employing TCA cycle and glycolysis to attain more energy, excessive needs for nitrogen, a higher rate of nutrient acquisition, metabolic interactions with the microenvironment, and dysregulation in metabolite-driven gene expression, which must be targeted to combat cancer [14]. In spite of clinical developments, and our understanding of the complex pathophysiological mechanisms of tumor metabolism as well as the interconnections among signaling pathways,

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cancer therapy remained a medical challenge. On the other hand, despite the importance of

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targeted therapy, most cancers could not be cured solely with single-target therapies, which raise the need for novel multi-targeted anticancer drugs. In this regard, recent advancements in finding

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novel signaling pathways involved in cancer progression and potential of plant secondary

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metabolites in targeting multiple signaling mediators in cancer metabolism underscore the use of these compounds for alternative, innovative, and effective therapeutic strategies [15, 16].

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Plant secondary metabolites are structurally diverse compounds with no direct participation in plant growth, development, and reproduction [17]. These metabolites are potential sources of

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new pharmacological mechanisms of action and novel chemical classes of drugs, possessing promising beneficial effects on human health [18]. Plant secondary metabolites have also attained special attention and have shown a new avenue in the treatment of cancer by targeting cancer metabolism and cross-linked pathways, including oxidative stress, inflammation,

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mutagenesis, and several other signaling mediators [19, 20]. Amongst numerous signaling pathways/mediators, phosphatidylinositol 3-kinases (PI3K), protein kinase B (PKB, also known as Akt), mammalian target of rapamycin (mTOR), hypoxia-inducible factor-1α (HIF-1α), extracellular signal-related kinase (ERK), mitogen-activated protein kinase (MAPK), nuclear factor-B (NF-B), activator protein 1, c-Jun NH2-terminal kinases (JNKs), signal transducer

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and activator of transcription (STAT), tumor necrosis factor receptor-associated factor (TRAF), TNFR1-associated death domain protein (TRADD), and Janus kinase (JAK), have shown to be auspicious therapeutic targets for natural secondary metabolites [21-27]. In a previous review, the authors presented studies on dietary phytochemicals targeting just the main pathways of deregulated cancer metabolism [28]. A limited number of other publications highlight the cross-linked signaling pathways of cancer dysregulation targeted by

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only a particular class of phytochemicals [29] or in a specific type of cancer [30, 31]. Moreover,

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the dysregulated mechanisms of cancer metabolism have also been described, with no focus on related cross-linked pathways or therapeutic effects of phytochemicals [32, 33].

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The objective of this review is to reveal all the major therapeutic targets as well as cross-

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linked signaling pathways in cancer metabolism. A promising anticancer perspective for plant secondary metabolites has also been described to find potential therapeutic agents in the

Dysregulated metabolism and signaling pathways in cancer

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2.

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treatment of cancer.

The altered metabolic pathways in cancer allow the cells to have a higher rate of proliferation even in the limitation of nutrient and oxygen [34]. There is growing evidence for the involvement of metabolic pathways and related interconnected signaling pathways in cancer

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reprogramming. Cancer reprogramming is an enhanced or suppressed conventional metabolic signaling pathways compared with normal cells. Moreover, cancer cells need to access high levels of glucose, fatty acids, amino acids, and nucleotides. Glucose, glutamine, lactate, pyruvate, acetate, and free fatty acids (FAs) are major catabolites providing the context for

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cancer progression. Due to the heterogenicity of cancer metabolism, tumor cells support different catabolites either by synthesizing or taking up from the circulation [35, 36]. These cross-linked signaling pathways, core metabolites, and related intermediates play a crucial role in the biosynthesis of carbohydrates, proteins, lipids, and nucleic acids as macromolecules. The cross-linked signaling pathways also determine the level of inflammation, oxidative stress, apoptosis and autophagy in cancer cells. Additionally, as the process of gene

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expression modification, epigenetic also plays a crucial role in cancer metabolism. Hence, the

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dysregulated metabolism of carbohydrates, proteins, lipids and epigenetic, as well as cross-linked

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pathways would be promising targets against cancer.

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2.1. Carbohydrate metabolism

As the most common fuel source of mammalian cells, glucose is a critical metabolic

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substrate for tumor progression. In this regard, tumor cells noticeably increase their glucose consumption [37]. As a crucial process in cancer reprogramming, the Warburg effect states that

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cancer cells produce lactate from the absorbed glucose as a substrate for mitochondrial oxidative phosphorylation, regardless of the availability of oxygen. This procedure of elevated aerobic glycolysis produces 36 more ATP per one glucose intake when compared to glucose oxidation through the TCA cycle in normal cells [38]. Hence, interfering with the transporters and enzymes

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of glycolysis and oxidative phosphorylation is of great importance to diminish cancer. Among them, glucose transporter (GLUT), hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), lactate dehydrogenase (LDH), pyruvate dehydrogenase (PDH), glyceraldehyde 3phosphate dehydrogenase (GAPDH), ATP citrate lyase (ACL), and monocarboxylate transporter 1 (MCT1), have been considered as promising targets against cancer [39, 40]. Among the rate-

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limiting regulatory enzymes in glycolysis catalyzing phosphorylation reactions, HK, PK, and PFK have shown to be highly regulated in cancer [32]. Glucose uptake and downstream lactate production pathways are increased in cancer cells. Additionally, various enzymes and mediators play critical roles in the glycolysis pathway. As an upstream regulator of glucose uptake, GLUT1 is more upregulated during cancer progression, which triggers glycolysis. The first step of glycolysis is catalyzed by HK, resulting in the

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conversion of glucose to glucose-6-phosphate (G6P). In this regard, HK could contribute to the

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production of lactate even in an aerobic situation which could be regulated by G6P [32, 41]. As another substrate for HK, 2-deoxyglucose is a competitive inhibitor of glucose, while it does not

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continue the glycolytic pathway [42]. PI3K/Akt/mTOR/HIF-1α, as the main cross-linked

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pathway in cancer, accelerates the activity of GLUT and HK [43]. So, HK and GLUT could be considered as a potential target against cancer progression. Continuously, in the glycolytic

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pathway, PFK catalyzes the conversion of fructose 6-phosphate (F6P) to fructose 1,6bisphosphate (F1,6BP) through the transfer of ATP phosphate group. ATP and PI3K could

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regulate PFK, where their high concentration inhibits and increases the glycolytic activity, respectively [44, 45]. As a tumor suppressor, p53 inhibits PFK and PEP. HIF-1α and MYC also activate the glycogenesis pathway by overactivation of GLUT, HK, and PFK. Several studies also introduced PFK inhibitors as promising agents against cancer. To continue downstream

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pathways toward the pyruvate production, F1,6BP can subsequently be converted to glyceraldehyde 3-phosphate and afterward 1,3-bisphosphoglyceric acid (1,3-BPG) by fructose 1,6‐bisphosphate aldolase and GAPDH, respectively. Besides, the inhibition of GAPDH could reduce the proliferation of cancer cells [46].

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PK catalyzes the final step of glycolysis. PK muscle isozyme M2 (PKM2), a dominant isoform of PK, is implicated in various cancers. Although PK plays a critical role in glycogenesis, tumors lacking PK still produce lactate from glucose, which suggests another noncanonical alternative pathway [47]. In this line, various studies have revealed the unnecessary role of PK with no-growth advantage in cancer development, and some others considered PK activation as an auspicious strategy to combat cancer [32, 48]. Furthermore, indigenously

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produced lactate makes a low acidic pH and a near interconnection with inflammation,

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immunosuppression, and immune escape mechanisms. The emerging evidence is also confirming that the microenvironmental acidity affects T cells, and natural killer (NK) cells and critical

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antigen-presenting cells, such as dendritic cells (DCs), tend to lose their function. In another

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way, the immunosuppressive components, including regulatory T cells and myeloid cells, are engaged by the acidic microenvironment, while the anticancer agents are blocked [49, 50]. This

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procedure leads to immune suppression, and therapy resistance, as well as fuel energetic and metastatic dissemination [51]. Emerging evidence revealed that buffering the tumor pH

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contributed to a recovery in the modulation of the aforementioned immune cells, followed by the attenuation of interconnected downstream signaling pathways to overcome drug-resistance [52]. In the glycolysis pathway, the produced pyruvate has two fates of converting to lactate or pyruvate dehydrogenase (PDH)-dependent oxidative decarboxylation. PDH converts pyruvate to

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acetyl-CoA, thereby release NADPH [53]. The regulation of PDH is of great importance in cancer therapy, where it is inhibited by pyruvate dehydrogenase kinase (PDK). It is worth noting that PI3K/Akt/mTOR/HIF-1α is the upstream activator of PDK [54]. Continuing this signaling pathway, succinate dehydrogenase (SDH) and fumarate hydratase (FH) along with other mitochondrial TCA cycle enzymes are involved in a series of reactions

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producing iso-citrate, citrate, α-ketoglutarate (α-kG), NADH and FADH2 [36]. The released sources of energy are used to be oxidized in the electron transport chain and restore ATP as energy [33]. Several mutations in the TCA cycle enzymes could accelerate the cycle reactions, thereby speed up cell growth. Additionally, the inhibitors of mutated enzymes showed new hopes in combating cancer [55]. Overall, the general stimulation of glycolysis as well as their related intermediates increases

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tumor growth, while their inhibition stops cancer proliferation. Nevertheless, not a single agent

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has yet been approved for the treatment of cancer.

The glycolytic cascade also allows the intermediates as well as the TCA cycle to affect

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macromolecule production or be affected by other signaling mediators, producing lipids, and

2.2. Protein metabolism

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TCA cycle, including glutamine.

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amino acids. To arrive higher energy there, tumor cells rely on other fuel sources to nourish the

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Amino acids are building blocks for proteins, fueling other signaling pathways in cancer metabolism [56]. In addition to the critical role of glucose in cancer metabolism, amino acids also play a fundamental role in cancer progression. As nonessential amino acids, glutamine and glutamate are crucial cell nutrient, involved in various catabolic and anabolic processes with key

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roles in TCA-dependent energy production as well as the nucleotide synthesis [57]. The upregulation of glutamine transporters (including SLC7A5 and SLC1A5) is an essential way towards resolving the problem of glutamate access by cancer cells [58]. The elevated level of glutamine synthesis and glutamine blood concentration has been shown in patients with cancer.

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Furthermore, relevant mitochondrial enzymes responsible for glutamine/glutamate oxidation are also increased in cancer cells [59, 60]. In addition to the promoting role of glutaminolysis on cellular proliferation, it also prevents cell death. Cancer cells meeting a much higher level of reactive oxygen species (ROS) than those in normal cells, which negatively affect the cell growth due to the oxidative damage to lipids, proteins, and nucleotides [61, 62]. Cancer cells supply a ROS balance via making an appropriate

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level of GSH and NADPH resulting from glutaminolysis which is critical for cancer cell survival

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[63, 64]. So, several tumor cells meet their anaplerotic needs through glutathione (GSH) oxidation to oxaloacetate [59]. In addition to the aforementioned role of glutamine, its fumarate-

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derivative increase glutathione peroxidase 1 (GPx1) and nuclear factor erythroid 2-related factor

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2 (Nrf2) involved in antioxidant signaling and ROS scavenging, respectively [65, 66]. In addition to the critical role of glutamine/glutamate in cancer growth, they play further

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characters in regulating other main actors of proliferation [67]. In this regard, glutamate synthase and glutamate dehydrogenase convert glutamine to glutamate and glutamate to α-kG,

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respectively. Noticeably, overexpression of MYC as a regulator gene could activate glutamate synthase leading to the glutamate-addiction in correspondence cancer cells [63]. Intriguingly, αkG itself is also converted to iso-citrate via iso-citrate dehydrogenase 1 (IDH 1), which can serve as a substrate for lipid synthesis [68, 69]. In the presence of a hypoxic condition or HIF-1α,

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glutamine could be also used as a substrate for the synthesis of FAs [69]. Interestingly, all cancer cells are not glutamine-addicted, which bring up oncogenic alterations that could elucidate glutamine dependence in some cancers. Due to the complexity of metabolic pathways in cancer, there is not enough information on the relationships between catabolic metabolism and metabolic flux in cancer cells. For instance,

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in spite of the low levels of glutamine (also glucose), there is a high level of pyruvate and lactate in some cancer cells. This could be either due to the inability of cancer cells in accessing glucose and glutamine or the rapid conversion of glucose and glutamine to the products (e.g., lactate and GSH) [70, 71]. Along with the critical role of glutamine and glutamate in cancer growth, other amino acids,

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such as tryptophan, are catabolized by indoleamine-2,3-dioxygenase and cause T-cell depletion and immunosuppression (via kynurenine production), thereby enabling tumor to escape from the

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immune system. So, targeting this enzyme could decrease tumor growth [72]. Accordingly, glutamine and glutamate play key roles in the production of several other amino acids, including

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asparagine, aspartate, arginine, alanine, and proline [59], and their overactivation could be found

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in different types of cancers [73]. In this line, the studies have shown that asparaginase could hydrolyze glutamine, thereby stop cell growth, in spite of serious side effects [74, 75]. Among

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other amino acids, serine and glycine not only served as building blocks of proteins but also donate carbon to the serine/glycine one-carbon (SGOC) metabolic network, thereby play critical

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roles in the synthesis of macromolecules [76, 77].

It is well known that targeting amino acids is a promising anticancer strategy against cancer and assessing the metabolic variables in cancer cells is also of a great importance for cancer therapy. Altogether, protein metabolism plays a critical role in the proliferation of cancer cells,

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and it is important for cancer cell survival.

2.3. Lipid metabolism Fatty acids (FAs) play key roles in the synthesis of lipid membrane as well as proceeding the signaling pathways. They also act as building blocks of the lipid metabolism pathway. In

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addition to carbohydrates and proteins, FAs are other critical needs for cancer progression, providing a new substrate to reach this goal. The increased levels of FAs in cancer cells as well as their elevated blood concentration have been shown in cancer patients. To achieve their higher need for FAs, cancer cells increase their synthesis and reduce their oxidation, breakdown, lipolysis, and re-esterification. This characteristic has been found in different types of cancer cells [78, 79].

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While the oxidation of FAs takes place in the mitochondria, FAs synthesis occurs in the cell

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cytoplasm with the contribution of special enzymes. As an abundant enzyme possessing multiple catalytic domains, FAS eases the synthesis of FAs. FAs are overexpressed in several cancer

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types with different sensitivities [80, 81], and accordingly, it could be an auspicious target to

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combat cancer. In the biosynthesis pathway of FAs, malate can be converted to acetyl-CoA, then malonyl-CoA by ACL and acetyl-CoA carboxylase (ACC), respectively. The overactivation of

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ACC and ACL has been observed in cancer cells. Knocking down ACL prevented the production of FAs, thereby inhibited cancer progression [82]. Interestingly, while several studies reported

[83, 84].

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that ACC inhibitors accelerate apoptosis, others show that ACC inhibition increased cell growth

While fatty acid synthase (FAS) is responsible for the synthesis of FAs, FA oxidation is responsible for the degradation of FAs. Even though most cancer cells usually prefer to have a

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reduced level of fatty acid oxidation, the opposite results are noticed in specific cancer types [85].

Overall, blocking FAs could be a promising anticancer regiment, while our understanding of

lipid metabolism needs to be refined.

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2.4. Epigenetics The process of gene interaction with products to express phenotypes was first presented by Conrad Waddington as the epigenetics concept. Epigenetics is the study of gene expression modifications with no changes in DNA [86], which includes both normal and abnormal cells, especially cancer cells [87, 88]. In the epigenetic level, several enzymes affect posttranslational DNA and histones modifications, leading to gene expression changes. The epigenetic alteration

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could happen during embryonic development [89] as well as childhood and could lead into

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adulthood [90, 91]. The interaction between cancer metabolism and epigenetic events leads to new insights into mechanisms of action of novel anticancer agents. The enzymes which are

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involved in the attenuation of epigenetic events are interconnected with other mediators and

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signaling pathways in cancer metabolism. Dysregulated cancer metabolism could strongly be associated with changes at the epigenetic level [92, 93]. The cancer-related alterations in gene

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expression result in the activation of oncogenes or inactivation of gene suppressors. Mutation in the enzymes of cancer metabolism as well as related cross-linked pathways could be upstream

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events, leading to epigenetic alterations [94]. In this regard, the cancer-related upregulation of HK isoform 2 (HK2) promotes the activity of GLUT, leading to its promoter hypomethylation [95]. Besides, the overactivation of PKM2 (PKM2) as the catalytic enzyme in the final reaction of glycolysis causes epigenetic-dependent cancer [96]. In the glycolytic pathway, PFK catalyzes

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the conversion of F6P to F1,6BP, and F1,6-BPase regulates glycolysis through affecting F1,6BP. F1,6-BPase has been found to be silenced through promoter methylation in various gastrointestinal diseases [97]. Mutational inactivation in various enzymes involved in cancer metabolism, such as IDH1/2 [98, 99], SDH [100] and FH [101], leads to the accumulation of hydroxyglutarate, succinate, and

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fumarate, respectively [102], which inhibits the DNA and histone demethylases activity at high concentrations [103]. In another study, a single mutation in SDH caused a potential genomic hypermethylation pattern in different types of cancer [104, 105]. A high concentration of a methyl donor methionine happens following a mutation in phosphoglycerate dehydrogenase (PHGDH) [106]. This mutation directs the glycolysis pathway toward the serine biosynthetic signaling, which modulates one-carbon metabolism [107]. Upregulation of N-methyltransferase

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(NMT) has been correlated with epigenetic mutation, elevated cell invasiveness and transfer of a

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methyl group from s-adenosyl methionine (SAM) to nicotinamide, impairing SAM-mediated methylation of DNA and histone [108].

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Overall, understanding the precise relation between epigenetics and major metabolic

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pathways in cancer provides new insights for developing novel anticancer agents. Fig. 1 shows the dysregulated signaling pathways in cancer metabolism and corresponding targets. Fig. 2

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displays the key role of lactate produced from dysregulated mechanisms (as depicted in Fig. 1)

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on immune suppression and tumor microenvironment.

2.5. Cross-linked signaling pathways

In spite of the complexity of genetic heterogeneity in cancers, several cross-linked pathways are implicated in cancer metabolism. For instance, the overactivation of the PI3K/Akt/mTOR

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signaling pathway happens with just little dependency on the extracellular stimulation. PI3K and Akt are among the main signaling molecules controlling cell metabolism through increasing glucose uptake and metabolism as well as lipid synthesis in cancer cells, whereas protein translation is more controlled by mTOR [109, 110]. As a key upstream modulator of mTOR, PI3K upregulates mTORC activity [111] following the binding of a growth factor to their related

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receptors, including platelet-derived growth factor receptor (PDGFR), insulin-like growth factor receptor (IGFR), or epidermal growth factor receptor (EGFR), resulting in the overactivation of several downstream signaling pathways, such as the PI3K/Akt and Ras/Raf/mitogen-activated protein kinase (MEK)-extracellular signal-regulated kinase (ERK)-ribosomal protein S6 kinase pathways [112]. PI3K activation catalyzes the conversion of phosphatidylinositol bisphosphate to phosphatidylinositol triphosphate. The PI3K/Akt/mTOR pathway as the main actor of cross-

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linked pathways in cancer metabolism could be inhibited by a protein/lipid phosphatase as well

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as phosphatase and tensin homolog (PTEN) [111]. Thus, Akt could be negatively ameliorated by PTEN and positively attenuated by PI3K [111-113]. As a result, the overactivation of PI3K

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resulted in the loss of PTEN, leading to the activation of Akt/mTOR, which has been shown in

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various types of cancers [114, 115].

Tumor cells also contain other mutations that overactive Ras/Raf/MEK/ERK/MAPK/JNK

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pathway, with minimal dependency on the IGFR, EGFR, insulin receptor and human epidermal growth factor receptor 2 (HER2) as upstream triggers [116]. As an upstream protein susceptible

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to mutation, Ras activates several downstream pathways, including ERK and MAPK. Besides, the TRAF/TRAD as well as JAK/STAT networks, there are also deregulated pathways during oncogenesis which all affect the cancer metabolism [117]. Following the PI3K stimulation, Akt also upregulates GLUT1/3, MCT4, LDHA, PKM2,

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and activates PFK as well as the mitochondrial association of HK1/2. The tumorigenic over activated pathways, especially PI3K/Akt/mTOR, upregulate several biosynthetic intermediates through core metabolic pathways of cancer, including glycolysis, TCA and PPP (especially G6PD). As a downstream mediator of PI3K/Akt, the mTORC1 also stimulates the glutamine uptake, glutaminase (GLS), and HIF-1α activation. Metabolic adaptation to a low-oxygen

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condition is organized by HIF-1α through increasing glycolysis. As major upstream activators of HIF-1α, mTOR and ERK play a critical role. The hyperactivated HIF-1α induced VEGF, PDK, HK, GLUT, LDH to induce glycolysis and angiogenesis [118], which is of the most common changes during cancer following the PI3K/Akt activation. Besides, MYC as another activator of glycolysis, attenuates the utilization and uptake of the glutamine and increases the expression of

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several genes involved in glycolysis in cancer [119]. Besides, amino acids provide cancer cells in protein synthesis and allow them to maintain

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the activity of mTORC1 in cancer progression. Glutamine could be synthesized from glucose and is a nitrogen donor agent for several metabolic enzymes that play critical roles in the

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mitochondrial membrane potential and TCA cycle [8]. As a protein degradation pathway in

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which produce enough energy and biomass to sustain proliferation, autophagy supplies amino acids for cancer cells, thereby contributes to some types of cancers which are inhibited by

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mTORC1 [120-122]. Overall, inhibiting glutamine synthesis as well as reducing glucose uptake by cross-linked pathways leads to the blockade of PPP, which then impairs nucleic acid synthesis

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[123].

Cancer cells also need glucose as a primary source of acetyl-CoA to produce FAs for lipid production and membrane synthesis [8, 124]. The increased rate of lipogenesis has been a suitable target in cancer. Sterol regulatory element-binding protein-1 (SREBP-1) and related

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enzymes, such as FAS and ACL (ATP citrate lyase), upregulate the key enzymes of lipogenesis, thereby are involved in the regulation of FAs and PPP, which are activated by mTORC1 and its related effector S6K [125]. From another mechanistic point of view, PI3K also activates the synthesis and inhibits the oxidation of fatty acids [126]. The overproduction of ROS activates core signaling pathways of cancer, including PI3K/Akt/mTOR/HIF-1α and ERK/MAPK, to

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promote oxidative stress and tumorigenesis. During cancer progression, cells elevate their antioxidant capacity to compensate for the elevated rate of ROS. Hence, disabling this antioxidant capacity may induce cancer cell death [61]. Among other regulators of mitochondrial metabolism, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) negatively or positively affects numerous signaling pathways

caspases) should be an auspicious way to combat cancer [73, 127, 128].

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in cancer. Hence, targeting mitochondrial oxidative stress and apoptosis (Bax, Bcl-2, and

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In another way, the loss of p53 (as a tumor suppressor) leads to the Warburg effect, promotes glutamine utilization and elevates glycolysis. Another checkpoint protein in the

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upstream of p53, the ATP sensor AMP-activated protein kinase (AMPK), provides cell survival

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and inactivates mTOR as a master regulator of cancer. Several tumor types encounter a lack of AMPK [129].

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Due to the complexity of the correlations between cancer metabolism and related crosslinked signaling pathways, understanding the precise interconnected pathways is of great

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importance. Figs. 3 and 4 show the main dysregulated cross-linked signaling pathways in cancer metabolism.

3.

Targeting cancer metabolism and related cross-linked pathways by synthetic agents

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In recent decades, as an auspicious strategy of developing selective anticancer agents,

conventional pharmacological targeting of cancer metabolism has attracted a lot of attention. The potential benefits of pharmacological therapy include the precise dosage titration as well as their identified pharmacokinetic and pharmacodynamic profiles. Among these agents, a few are

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approved by the United States Food and Drug Administration (FDA), and several others are in the preclinical/clinical stages of development. To support their unusual rate of cell proliferation, cancer cells need excess energy, thereby depend substantially on glycolysis, glutamine metabolism, FAs, proteins, and epigenetic changes [130]. As one of the most critical resources of energy in cancer cells, glycolysis has attained special attention [131]. Targeting particular mediators and enzymes of this pathway, including

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those involved in glucose transport and glucose breakdown has been a new strategy in combating

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cancer. Compelling evidence supports these enzymes as hopeful candidates with encouraging results in preclinical/clinical models of cancer. Targeting glycolysis in cancer metabolism can

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impair bioenergetics by limiting the pathways of supplying nutrients to the cell and stopping an

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adaptive response to stress. In this line, ritonavir and phloretin have restricted glucose uptake by cancer cells through targeting GLUT, thereby have lowered the glycolysis rates and cancer

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development [132].

Of the second step of glycolysis, 2-deoxy-d-glucose (2DG) is phosphorylated by HK to

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produce 2-deoxyglucose-6-phosphate, a competitive inhibitor of G6P metabolism, thereby halting cancer growth with toxicity. In this line, 3-bromopyruvic acid, lonidamine, and methyl jasmonate have also been shown to be promising agents to target HK in preclinical and clinical stages [133-136].

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While the inhibition of PFK has shown to be a promising anticancer strategy in vitro [137],

PKM2 inhibitors are potential anticancer agents in vitro, in vivo, and in clinical studies [39, 138]. Oxamate inhibits LDH, the enzyme of converting pyruvate to lactate, thereby reversing LDHassociated resistance against paclitaxel in several cancer types [139]. Galloflavin also showed anticancer effects in preclinical studies by targeting LDHA [140]. Another anticancer agent,

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dichloroacetate (DCA), inhibits PDK1 which is an overactivated enzyme in cancer cells. DCA has shown potential anticancer activities against glioblastoma and non-Hodgkin’s lymphoma through attenuation of lactate secretion/uptake by targeting MCT4 and MCT1 [141]. As an antidiabetic agent, metformin also exerts a promising anticancer effect through targeting mitochondrial respiration and interfering with mitochondrial complex I in patients with pancreatic, prostate, and breast cancer [39]. Arsenic trioxide also showed anticancer effects in

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the preclinical and clinical studies of acute promyelocytic leukemia, through targeting

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mitochondrial complex III [142]. Besides, aminoglycosides and oxazolidinones, as well as tigecycline and doxycycline have also shown in vivo anticancer effects through targeting

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mitochondrial ribosomes and mitochondrial protein translation, respectively [143, 144].

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As previously mentioned, cancer cells also need to access high levels of lipids, amino acids, and nucleotides [145]. From the amino acid points of view, glutamine, glutamate, aspartate, and

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arginine are nonessential amino acids, which are crucial for cell nutrient. In this regard, Lasparaginase is a FDA-approved drug acting through reducing the availability of asparagine in

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acute lymphoblastic leukemia cells. In another report, a pegylated arginine deiminase also exerted a promising anticancer effect through converting L-arginine into L-citrulline. Inhibiting glutaminolysis by GLSs inhibitor reduced the glioblastoma cell growth [39, 146]. From the lipid metabolism point of view, targeting FAS inhibitors has shown anticancer

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effects [147]. In this line, while cerulenin induced apoptosis, orlistat showed cytostatic and cytotoxic effects in vivo and in vitro. In the preclinical studies, hydroxycitrate and betulin have indicated anticancer effects by targeting ACL and SREBP, respectively, thereby inhibited fatty acid synthesis [148, 149].

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Targeting nucleic acid synthesis as well as the pentose phosphate pathway also leads to the inhibition of DNA synthesis in several cancer cells. Accordingly, dehydroepiandrosterone (DHEA), as an inhibitor of rate-limiting G6PDH enzyme, reduced the ribose-5-phosphate (R5P) level, and nucleotide biosynthesis. In this regard, oxythiamine also inhibited the activity of transketolase and induced apoptosis in colon cancer [150]. Methotrexate, pemetrexed, and

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pralatrexate act by inhibiting dihydrofolate reductase in the synthesis of nucleic acid [151]. Previously, 5-fluorouracil, capecitabine, pentostatin, cladribine, 6-mercaptopurine, cytarabine,

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gemcitabine, and fludarabine have been shown to exhibit anticancer effects mediated through inhibition of nucleic acid synthesis [152].

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From another mechanistic point of view, compelling evidence also suggests a near link

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between the aforementioned dysregulated metabolic pathways and cross-linked pathways. As a critical signaling pathway, PI3K/AKT/mTOR plays a critical role in human health. The

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dysregulation/overactivation of this pathway contributes to several human cancers, which happens in about two-third of breast cancers. So, developing small molecule inhibitors to target

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PI3K, Akt or mTOR is of great importance [153, 154]. As PI3K inhibitors, pictilisib and buparlisib could stop the progression of breast cancer in combination therapies with fulvestrant [155, 156]. Besides, these PI3K inhibitors are also to be evaluated in clinical trials of non-small cell lung cancer (NSCLC) [157, 158]. Several other PI3K inhibitors are in preclinical and clinical

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stages [158, 159]. As a downstream mediator of PI3K/Akt, mTORC1 also attenuates protein translation, thereby plays key roles in glucose and lipid metabolism [160]. Targeting the upregulated mTOR in several cancer types is an optimistic strategy to combat cancer by inducing apoptosis and suppressing protein synthesis and translation [161, 162]. In this regard, rapamycin, temsirolimus, and everolimus have been approved to treat acute myeloid leukemia, renal cell

20

carcinoma, and breast cancer, respectively [153, 162]. In addition to pan-PI3K inhibitors and pan-mTOR inhibitors, there are also dual PI3K/mTOR inhibitors used in solid tumors. For instance, dactolisib, apitolisib, and gedatolisib as dual PI3K/mTOR are in clinical phases for evaluation against various cancer types [158]. Metformin and aspirin have also been provided as anticancer agents through targeting cross-linked signaling pathway in cancer metabolism. Metformin can, therefore, potentially target different metabolic pathways that are associated with

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cancer progression and proliferation by inhibiting mTOR and activating AMPK [163]. In a

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parallel path, the overactivation of tyrosine kinase receptors (e.g., HER2, and EGFR) [164] as well as related downstream signaling pathway, Ras/Raf/MEK/ERK/MAPK, are known to occur

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in cancer. While lapatinib is a FDA-approved tyrosine kinase inhibitor targeting both HER2 and

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EGFR [165], erlotinib and gefitinib are EGFR inhibitors with approval in cancer [166]. Hence, targeting tyrosine kinase receptors and downstream signaling pathways open a new avenue in

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cancer therapy.

In addition to oncogenic signaling pathways, tumor suppressor loss is another predisposing

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agent in cancer progression. While p53 is a critical regulator of apoptosis and Warburg effect through inhibiting glucose flux, its mutation has been shown in about half of the cancer types [167]. In this line, several p53 reactivators (e.g., chetomine) and heat-shock protein-90 (HSP-90) inhibitors are being to be evaluated in clinical phases for solid tumors [168]. Accordingly, the

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inhibition of histone deacetylases (HDAC) has also been a novel way in cancer therapy by preventing the complexing of p53 and HDAC. As a HDAC inhibitor, vorinostat has been approved for the treatment of cutaneous T cell lymphoma [169]. As another critical tumor suppressor which inhibits the aforementioned PI3K/AKT/mTOR pathway, PTEN is absent in about 40% of tumors, which leads to tumor growth [170, 171]. As a critical inflammatory

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mediator in the downstream of the PI3K/Akt pathway, NF-B also showed to be regulated by synthetic agents, such as simvastatin (an antihyperlipidemia drug), thereby exerted therapeutic effects in cancer-related bone loss [172]. Accordingly, blocking NF-B has been also as a promising strategy in overcoming chemoresistance in cancer by natural statins, especially simvastatin [173].

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Overall, targeting oncogenic and cross-linked signaling pathways seems to be a promising

4.

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approach for cancer therapy.

Anticancer plant secondary metabolites and their targets

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As previously described, natural bioactive compounds have been used for the treatment of

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several cancer types [28, 174]. These secondary metabolites with diverse chemical structures act as potential multi-targeted anticancer agents. Traditional and alternative medicinal plants have

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opened a new avenue in developing novel anticancer lead structures and lead compounds to offer novel and promising anticancer agents. Several natural secondary metabolites have exhibited

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considerable therapeutic effects in cancer treatment [175, 176]. In this regard, phenolic compounds, terpenoids, alkaloids, and sulfur-containing compounds have shown to possess promising anticancer activity [15, 177-183]. As a main class of secondary metabolites, polyphenols and phenolic compounds have

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shown their anticancer effects through different mechanisms of affecting inflammatory, oxidative and apoptosis-related pathways [184]. The promising in vivo and in vitro results of phenolic compounds in cancer prevention urge the need to reveal their inhibitory effects on cancer metabolism. In this regard, phenolic compounds have shown a potential inhibitory effect on GLUT [185-187], HK [188], G6PD [189, 190], PFK, PK [191], FAS [192], and PDH [193] in

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different types of cancer [28]. Further results on mechanistic studies reveal that phenolic compounds suppress cell proliferation through the inhibition of PI3K and Akt. Polyphenols also inhibited mTOR and NF-B as downstream mediators of the PI3K/Akt pathway [194]. Besides, phenolic compounds have shown to provoke apoptosis in cancer cells by inhibiting Bcl-2 and activating Bax, caspase-3, and caspase-8. Several phenolic compounds also block cancer

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proliferation by targeting Wnt and STAT3 [195-197]. Polyphenols also target the beclin-1, atg5, and atg-7 as molecular mediators involved in autophagy [198]. Polyphenols exert their growth

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inhibitory effects through increasing the expression of ERK, p38MAPK, and JNK1/2/3 in the apoptotic pathway, while reduced Ras/Raf/MEK/ERK/MAPK and JNK1/2/3 in the transcription

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pathway [30, 199]. The anti-inflammatory effects of some other polyphenols were exerted

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through blocking the expression of NF-B and other inflammatory cytokines (e.g. IL-6, TNF-α, and COX-2), thereby showed encouraging anticancer effects [200, 201]. In this regard, the

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arachidonic acid pathway and related mediators have been introduced as critical dysregulated pathways/agents targeted by natural secondary metabolites [202]. These secondary metabolites

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also showed to modulate other critical signaling pathways and mediators involved in cancer. As another class of natural secondary metabolites, terpenoids (also known as isoprenoids) are other plant-derived compounds, possessing a wide range of promising anti-inflammatory, antioxidant, neuroprotective, and anticancer effects. These compounds exert their therapeutic

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effects through targeting major cancer metabolic pathways (e.g., ACC1, PKM2, enolase, HK, and GLUT) and cross-linked pathways (PI3K/Akt/mTOR/AMPK) [203]. Terpenoids have also shown promising anticancer effects through reducing the levels of GLUT, HK, MDH, FAS, HK, and PK [204-206]. Besides, these phytochemicals have also shown to trigger apoptosis and autophagy through the upregulation of correspondence mediators. Terpenoids also target the

23

beclin-1, atg5, and atg7 as molecular mediators involved in autophagy [198]. Additionally, terpenoids have shown to provoke apoptosis in cancer cells by inhibiting Bcl-2 [28]. As other naturally-occurring molecules with a basic nitrogen atom in their structure, alkaloids are of the potent anticancer agents [181]. Alkaloids regulated the overexpression of GLUT, LDH, PFK, PK, and Fas, which were involved in their anticancer effects. Also, alkaloids interfere with p53 and MAPK/caspase-3, thereby hindering tumor growth. These natural

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compounds also target the beclin-1, atg5, and atg7 as molecular mediators involved in autophagy

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[198].

Other plant-derived active compounds, such as sulfur-containing secondary metabolites, are

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found in many plant species. Compelling evidence supports the promising effects of sulfur-

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containing secondary metabolites in health and disease. Especially, they have shown a bright future in combating cancer owing to their role in the prevention of epigenetic mechanisms in the

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initiation of carcinogenesis, including the histone modification and the attenuation of DNA methylation [207]. In addition, these compounds target glycolysis as well as cross-linked

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signaling pathways. Accordingly, the main targets of sulfur-containing secondary metabolites are p53, Bcl-2 [208], Bax, caspase-3, caspase-9, NF-κB [209], ROS [210], STAT5 [211], Nrf2 [212], COX-2, MMP-9, VEGF, ERK1/2, and LDH production [213-216] which are involved in the process of apoptosis, inflammation and oxidative stress [211]. So, sulfur-containing

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secondary metabolites could be of great importance in targeting cancer metabolism to combat several cancer types. Altogether, plant kingdom has been introduced as one of the best sources of new anticancer

agents.

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5.

Targeting cancer metabolism and related cross-linked pathways by phytochemicals

5.1. Preclinical (in vitro and in vivo) studies

5.1.1 Phenolic compounds As a group of multi-targeted secondary metabolites, phenolic compounds have shown a wide range of biological activities against several diseases. These molecules represent plant

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secondary metabolites, possessing antioxidant, anti-inflammatory and apoptosis-inducing effects,

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thereby displaying a substantial health-promoting potential in many areas. Upregulation of tumor suppressor genes, promoting apoptosis, inhibition of signal transduction pathways, cell cycle

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arresting, disturbance of angiogenesis, enhancement of GLUT1 mRNA levels, reduction of lipid

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synthesis, FAS activity, and glycogen synthesis are the most common mechanisms and metabolic dysregulations used by phenolic compounds against cancer cells [28, 217]. Various phenolic

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tumor cells.

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compounds have shown promising anticancer effects though modulation of metabolic activity in

5.1.1.1 Curcumin

Curcumin (Fig. 5) is one of the most important natural polyphenols derived from Curcuma longa L., possessing a particular chemical structure responsible for significant therapeutic

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effects, such as anticancer and anti-inflammatory activities. It has been shown that curcumin could induce the apoptotic mechanism via an interferon-induced protein with tetratricopeptide repeats 2 (IFIT2)-dependent pathway in human leukemic cell lines [218] (Table 1). In this in vitro model, U937 human leukemic cells exposed to curcumin showed reduced expression of Bcl-2, while enhanced expression levels of cleaved poly-ADP-ribose polymerase 1 (PARP-1)

25

and caspase-3 were noticed [218]. To investigate the in vitro and in vivo effects of curcumin on the head and neck squamous cell carcinoma, an ataxia telangiectasia-mutated gene (ATM)/Chk2/p53-dependent pathway was proposed for its anticancer mechanism of action [219]. Furthermore, the inhibition of IGF2 and IGF2-mediated PI3K/Akt/mTOR signaling [220], induction of apoptosis via ROS-mediated p53 and Akt [221] and suppression of Wnt/β-catenin [222] signaling pathways have been reported as related mechanisms of curcumin’s anticancer

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effect. In this regard, ameliorating AMPK/mTORC1 signaling pathway [223], inhibiting the

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ATP-synthase activity [224], decreasing the expression of the transcription factor EGR-1 and cancer-associated microRNA, reducing the activity of CDK2 [223] and targeting NF-κB [225]

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are among other proposed mechanisms for the anticancer effects of curcumin. In addition to the

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aforementioned cross-linked pathways in cancer metabolism, curcumin also interfered with various biosynthetic and energetic dysregulated metabolism in cancer, such as down-regulation

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of PKM2 leading to a reduction in the Warburg effect in diverse cancer cell lines [226],

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inhibition of the activity of FAS [227], and decrease of polyamine biosynthesis [228].

5.1.1.2 Resveratrol

Resveratrol, a natural phytoalexin polyphenolic agent from the stilbene class, is mainly isolated from peanuts and grape skins. Previous studies emphasized that resveratrol showed a

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suitable antitumor activity through the induction of sirtuin 1-dependent apoptosis [229]. Moreover, in vitro and in vivo and studies proposed that targeting and interfering with the hepatocyte growth factor/c-Met signaling pathway is the main mechanism of resveratrol in suppressing human hepatocellular carcinoma [230]. Another in vitro investigation of resveratrol on human colon cancer cells showed that resveratrol exerted a significant anticancer activity through modulation of PI3K/Akt signaling pathway [231]. Resveratrol-loaded gold nanoparticles 26

facilitated the apoptosis via upregulating Bax and caspase-8 as well as down-regulating procaspase-3, pro-caspase-9, and PI3K/Akt in human liver cancer cell line (HepG2). It also significantly increased tumor apoptosis, suspended tumor growth, and diminished the expression of VEGF in tumor tissue, thereby suppressed cancer in vivo [232]. The TRAF/NF-κB is also another suggested anticancer pathways for resveratrol to inhibit the migration and growth of prostate cancer [233, 234]. Interfering with various cross-linked cancer metabolic pathways, such

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as chemokine pathways [235], increasing ROS production, enhance the p53 expression,

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interfering with the TGFβ1/SMAD [236], and inhibiting SREBP1 [237] are among the other proposed anticancer mechanisms of resveratrol. From the cancer metabolism point of view,

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resveratrol inversed the Warburg effect through targeting the PDH [238], inhibiting GLUT [239],

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attenuating HK2-mediated glycolysis [240], and decreasing the FAS protein level and

5.1.1.3

Quercetin

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lipogenesis [241, 242].

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Quercetin, a bioflavonoid found in various vegetables, fruits, and medicinal plants, exhibits antioxidant, anti-inflammatory, and anticancer activities [243]. Quercetin exerted promising anticancer effects through a variety of pathways, including down-regulation of p53, G1 phase arrest, inhibition of tyrosine kinase and heat shock proteins as well as the suppression of Ras

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protein [244]. Combination therapy of quercetin with metformin could significantly suppress the prostate cancer cells through the inhibition of PI3K/Akt/VEGF signaling pathway [245]. In vitro and in vivo studies indicated that quercetin notably reduced the viability and proliferative activity of human melanoma cell lines through JNK/p38-MAPK signaling pathway [246]. Targeting and interfering with the Snail-independent ADAM9 expression and Snail-dependent Akt activation

27

pathways are the main preclinical mechanisms of quercetin implicated in the suppression of metastatic behavior of lung cancer cells [247]. In addition, the activation of apoptosis and autophagy was proposed as a targeted cross-linked pathway for the anticancer effects of quercetin in colorectal lung metastasis and hepatocellular carcinoma [248, 249]. Besides, quercetin targeted and interfered with tumor metabolism via suppressing FAS [250] as well as inhibiting the lactate production and glucose uptake by reducing GLUT1 mRNA levels and

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Naringenin and naringin

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5.1.1.4

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decreasing the GLUT1 cytoplasmic fraction [251].

Naringenin and naringin (naringenin 7-O-neohesperidoside) are well-known and important

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flavonoids present in various plants. The cytotoxic effects of these compounds (especially naringenin) have frequently been reported against various cancer cell lines. Evaluation of the

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effects of naringenin on JEG-3 and JAR human placental choriocarcinoma cells showed that naringenin inhibited the growth of these cells through JNK/MAPK and ROS-mediated apoptotic

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pathways [252]. Additionally, naringenin inhibited the migration of breast cancer cells through interfering with apoptotic cell signaling pathways [253]. Similarly, naringin inhibited the migration and invasion of human glioblastoma cells through the attenuation of p38-MAPK and down-regulating the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 [254].

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Inhibiting and interfering with the FAK/MMP activity is another mechanism for the anticancer effect of naringin against glioblastoma [255].

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5.1.1.5 Miscellaneous polyphenols Silymarin [256], chrysin [257], daidzein [258], apigenin [259], pelargonidin [260], malvidin [261], gallic acid [262], and morin [263] are also some of the other polyphenolic compounds with in vitro and in vivo anticancer activity against different types of cancer. In particular, morin down-regulated cyclin D1, COX-2, MMP-9 and NF-κB in human lung carcinoma (A549),

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human epithelial carcinoma (HeLa), and human neuroglioma (H4) cells [264].

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5.1.2 Terpenes and terpenoids

Terpenes are a group of secondary metabolites found in various plants and animals, insects,

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and microbe species, possessing anti-inflammatory, antibacterial, anticancer, and neuroprotective

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activities. Terpenes are made of the isoprene unit (2-methyl-1,3-butadiene; C5), and terpenoid refers to the modified category of terpenes with diverse functional groups, and oxidized methyl

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group removed or rotated at variant positions [265]. Based on the number of isoprene units present in their molecule structure, terpenes can be classified into several categories, including

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monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes. These compounds exert their anticancer effects by lowering the levels of FAS and fatty acid contents, decreasing lactate and ATP production, and reducing glucose uptake as well as the levels of GLUT1 and enolase mRNA. They also reduced the level of variant proteins, such as ACC1, PKM2, MMP-2, MMP-9,

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Bcl-2, HK2 and NF-κB signaling and nuclear transfer of c-Jun/c-Fos, while upregulated the p53 expression [28, 266].

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5.1.2.1 Monoterpenes and sesquiterpenes Monoterpenes are a category of terpenes, composing of two isoprene units, possessing the molecular formula C10H16. Carvacrol, limonene, myrcene, and geraniol are various well-known compounds of this class with significant anticancer activity [206, 267]. Carvacrol controlled the invasion and also decreased the cell survival, and proliferation of human PC-3 prostate cancer

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cells line through reducing the IL‑ 6 gene expression, and diminution of p-STAT3, p-ERK1/2, and p-AKT signaling proteins [268] (Table 2). In a similar study, a novel nanoemulsion of

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carvacrol showed significant anticarcinogenic activity against human lung adenocarcinoma through increasing the generation of ROS inside the mitochondria [269]. Another in vitro study

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on carvacrol showed promising effects on human colon cancer and gastric adenocarcinoma cells

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by regulating PI3K/Akt and MAPK signaling pathways, reducing the expression of MMP-9 and MMP-2 and increasing apoptosis and ROS production [270, 271]. Geraniol, in combination with

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β-ionone, could suppress the proliferation and induce arrest of MCF-7 breast cancer cells [272]. From the cancer metabolism point of view, geraniol decreased the metabolism of fatty acid,

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reduced HMGR mRNA and protein levels, inhibited the mevalonate pathway (the main pathway of cholesterol biosynthesis resulting in mevalonate) and phosphatidylcholine synthesis, and increased the level of p-ACC [273, 274]. Sesquiterpenes make a structurally diverse family of hydrophobic molecules with a

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molecular formula of C15H24. They consist of three isoprene units and maybe acyclic or contain rings in their structures (like monoterpenes) [275]. Sesquiterpene lactones and cadinene are two important branches in the category of sesquiterpene. Among them, isobutyroylplenolin, arnicolide D, zerumbone, cacalol, and dimethylaminomicheliolide (DMAMCL) are some of the sesquiterpenoid compounds, which exert their anticancer effects through various mechanisms.

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The activation of caspase-3, induction of apoptosis, inhibition of the anaerobic metabolism, reducing the lactate production, modulating the FAS and PKM2 activity, ROS, NF-B and AktSREBP signaling pathways are among the most important mechanisms of sesquiterpenes against cancer [276-279].

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5.1.2.2 Diterpenes, triterpenes, and tetraterpenes From the combination of four, six, and eight isoprene subunits, diterpenes (C20H32),

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triterpenes (C30H48), and tetraterpene (C40H64) can be achieved, respectively. In addition to the antibacterial, antifungal, and anti-inflammatory activities of terpenes, these isoprene subunits

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exhibited specific anticancer effects [267]. Several diterpenes, such as forskolin, grayanotoxin,

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14-deoxyandrographolide, eleganolone, and marrubenol, have shown potential therapeutic effects [280]. In this regard, taxanes are a class of diterpenes that are one of the main drugs used

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to treat cancer. Taxanes first derived and isolated from the bark of the Yew tree. Afterward, semisynthetic derivatives have been developed and documented to be a very important option to

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impede the growth of cancer. The docetaxel (Taxotere®), paclitaxel (Taxol®) and recently developed cabazitaxel (Jevtana®) were approved by the FDA to treat variant cancers [175]. As a major class of secondary metabolites, triterpenes have many methyl groups (R-CH3), which can be oxidized into carboxylic acids, aldehydes, and alcohols. This feature makes these compounds

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more complex and also biologically different [280]. Andrographolide, carnosol, triptolide, ursolic acid, escin, glycyrrhizic acid, celastrol, alisol, lycopene, and β-carotene are several compounds in this category, exhibiting significant antitumor effects. Triptolide, a diterpenoid triepoxide, is isolated from the Tripterygium wilfordii. Several studies have revealed the remarkable anticancer potential of triptolide in the management of

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various cancers [281]. Triptolide has shown to suppress the migration and proliferation of esophageal squamous cell cancer in vitro and in vivo, via interfering with the MAPK/ERK signaling pathway, induction of apoptosis and G1/S cell cycle arrest [282]. In a recent study, the efficiency of triptolide, in combination with cisplatin, was investigated in the treatment of triplenegative breast cancer (breast cancer that lacks estrogen receptor, progesterone receptor, and HER2). In this study, triptolide could successfully repress the growth of two triple-negative

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breast cancer cells, BT549 and MDA-MB-231. Down-regulating the levels of XRCC1 and

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PARP1, sensitizing cancer cells to cisplatin, induction of the S phase cell cycle arrest, and DNA breaks, and reducing the levels of RAD51 were the dominant anticancer mechanisms of

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triptolide [283]. Triptolide also induced considerable cytotoxicity against NSCLC via facilitating

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the apoptosis and down-regulating the phosphorylation of mTOR, Akt, and p70S6K in crosslinked pathways with cancer metabolism. Triptolide also influenced cellular glycolysis via

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impairment of glucose utilization, with a parallel decrease in the levels of glutathione (GSH), HK2, and Nrf2 [284]. Inhibiting Nrf2-ARE activity, interfering with caveolin-1/CD147/MMPs

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and miR-141-3p/PTEN/Akt/mTOR pathways, induction of G1 phase arrest via upregulation of p21, and altering key flux ratios of glucose metabolism are other proposed antitumor mechanisms of triptolide [285-288].

Carnosic acid is another diterpene that has been studied for probable anticarcinogenic

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effects on LLC lung cancer, B16F10 melanoma, and CT26 colon cancer cell lines. It has been reported that carnosic acid showed its anticancer activities by up-regulating E-cadherin and down-regulating N-cadherin and vimentin. In addition, carnosic acid could upregulate the TIMP2, and down-regulate the MMP-9, and VCAM-1 and inhibited the activation of Src, FAK, and Akt [289]. Kahweol, andrographolide, geranylgeranoic acid, oridonin, and pseudolaric acid B are

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some of the other diterpenes, diterpenoids, and isoprenoids with anticancer effects on various cell lines, such as HT-29, MV4-11, A549, HuH-7, SW480, and MUM2B [290-296]. Ursolic acid is another well-known triterpene that has been investigated for its anticancer effects on many cancer cell lines. Park et al. [297] designed a study to investigate the beneficial effects of ursolic acid in suppressing cancer cell proliferation. The results showed that ursolic acid induced apoptosis via activation of caspase and inhibition of the Wnt5/β-catenin pathway in

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PC-3 prostate cancer cells. To improve the pharmacokinetics of ursolic acid, nano-formulation of

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this compound was designed and synthesized, which also showed a higher potency to inhibit cell proliferation and induce cell cycle arrest at the G2/M phase in HepG2 cells [298]. Due to the

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potential effects of ursolic acid in interfering with the glycolytic pathway, it could promote

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apoptosis and autophagy in the various breast cancer cell lines [299]. Ursolic acid also exerted its anticancer effects through the suppression of an inflammatory chemokine receptor, CXCR4, in

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prostate cancer in vivo and in vitro [300]. Tubeimoside-1, plectranthoic acid, pachymic acid, cucurbitane, avicins, oleanolic acid, ginsenoside, α-hederin, and betulinic acid are some of the

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other compounds in the terpenes class that impart their anticancer effects by affecting Aktmediated pathway, mTOR/S6K signaling, PKM2, and glucose metabolism, activating AMPK, and PPAR-𝛾, targeting mitochondrial membrane, suppressing aerobic glycolysis, decreasing the production of lactate, and inhibiting the activity of stearoyl-CoA-desaturase [301-311].

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In a study by Xiaoming et al. [312], β-carotene, a tetraterpene, could significantly inhibit

the synthesis of cholesterol and cell growth in MCF-7 cells. In a similar study, β-carotene facilitated the apoptosis and ROS production, while up-regulated the expression of the p21 gene and PPAR-𝛾 in the same cell line [313]. In another study by Chalabi et al. [314], the effect of lycopene (another tetraterpene) on MCF-10a fibrocystic mammary cell line and breast cancer

33

cell lines (MDA-MB-231 and MCF-7 cell lines) was investigated by employing pangenomic arrays. Results suggested that lycopene could upregulate 30 and down-regulate 26 genes, which are involved in the cell cycle, apoptosis mechanism, biosynthesis of fatty acid, MAPK signaling, and xenobiotic metabolism. Lycopene has been shown to suppress the proliferation of androgenindependent prostate cancer cells (DU-145 and PC-3 cell lines) through the PPARγ-LXRαABCA1 pathway. Besides, lycopene increased the cholesterol efflux and thereby caused a

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diminution of the cellular cholesterol and incremented cholesterol in the culture medium [315].

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Lycopene showed its antiproliferative effect via various mechanisms, including a decrease in the levels of cyclin E, cyclin D1 and cyclin-dependent kinase 4, blockade of the G1/S transition,

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induction of G0/G1 cell cycle arrest, and inhibition of the activation of Akt in LNCaP and PC-3

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cell lines [316]. Additionally, the beneficial effect of lycopene oxidation products on cell viability of different cancer cell lines, such as MCF-7, PC-3, A431, HeLa, A549 and HepG2,

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was investigated. The results showed that lycopene could enhance the MDA and ROS levels

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while depleting the GSH level [317].

5.1.3 Alkaloids

Alkaloids are plant-derived organic compounds possessing basic nitrogen atom(s) in their heterocyclic ring(s). Alkaloids are typically basic compounds with a widespread distribution in

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the plant kingdom, primarily available in most plants known by the family Leguminosae, Ranunculaceae, Papaveraceae, Loganiaceae, and Menispermaceae [283]. While alkaloids could be found in fungi, animals, and bacteria, the main sources of common alkaloids are plants. Alkaloids are amongst the most important active components with several substantial pharmacological and biological effects in cancer, acute bronchospasm, narcolepsy, and

34

anesthesia-induced hypotension. The antitumor effects of these compounds against various cancers are prominent. Several alkaloid compounds are FDA-approved anticancer drugs, such as vinblastine (a tubulin/microtubule formation inhibitor) and camptothecin (topoisomerase I inhibitor) [284, 285]. The following section introduces some of the recent studies that investigated the anticarcinogenic mechanisms of alkaloids and their derivatives on different cell lines or models.

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The in vitro and in vivo effects of a benzylisoquinoline alkaloid berberine (Fig. 6) on gastric

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carcinoma, glioblastoma, and colon cancer cell lines were investigated. The ameliorating effects of berberine on the AMPK/HNF4a/Wnt5A and AMPK/mTOR/HIF-1α/ULK1 pathways were

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suggested as the main mechanisms of berberine to induce autophagy and diminish the

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proliferation, migration, and invasion of various cancer cell lines [318-320] (Table 3). Besides, it was also reported that berberine could suppress the growth of breast and colorectal carcinoma

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cells by participating in the homeostasis, metabolism, and balancing the activity of tumor PKM2 [321, 322]. Inhibiting the proliferation of cancer cell lines through energy depletion and

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disruption in protein response is another effect of berberine [323]. Furthermore, tomatidine is another glycoalkaloid that suppressed the invasion of the cell via inactivation of ERK and p38 as well as down-modulation of gelatinase [324]. As another promising alkaloid, phellodendrine chloride is one of the active components of Phellodendron extract that showed a considerable

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potency via reducing the viability of PANC-1 and MiaPaCa-2 cell lines [325]. Recently, Xu et al. [326] demonstrated the significant in vitro and in vivo anticancer effects of bouchardatine on rectal cancer through interrupting the metabolic pathways by activating the cross-linked pathways of cancer metabolism, including SIRT1/PGC-1α/UCP2 axis. Disrupting and interfering with PI3K/Akt/mTOR as the main cross-linked pathway in cancer metabolism as well as

35

suppressing the VEGF-mediated angiogenesis was considered as main antitumor mechanisms of another alkaloid, 4-chloro fascaplysin [327]. Piperlongumine suppressed the thioredoxin and GSH systems and consequently increased the production of ROS and decreased the resistance of colorectal cancer cells to radiation. Piperlongumine also induced apoptosis via suppression of PI3K/Akt/mTOR signaling pathway in human triple-negative breast cancer cells [328, 329]. In this line, an alkaloid derivative of the lotus plant, neferine, inhibited the lung cancer that was

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induced in Wistar rats via diminishing the gene expression of the PI3K/Akt/mTOR signaling

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pathway [330]. Following the anticancer effects of alkaloids, the in vitro and in vivo investigation of a quinolizidine alkaloid, aloperine, showed its ability of inducing G2/M cell

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cycle arrest and facilitating apoptosis via suppression of the PI3K/Akt signaling pathway [331].

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Dihydrosanguinarin has been found to regulate the activity of Ras/Raf/MEK/ERK and mutp53/WT-p53 pathway, thereby inhibiting the growth of pancreatic cancer cells (SW1990 and

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PANC-1) [331]. Besides, tetrandrine (a bisbenzylisoquinoline alkaloid) could successfully suppress the proliferation of SW620 (colon cancer cell line)

through interfering with

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PI3K/AKT/PTEN signaling pathway [332]. Nitidine chloride induced apoptosis and suppressed the growth, migration, and invasion of osteosarcoma cells via the down-regulation of SIN1 [333]. Additionally, piperine, capsaicin, N-methyl-hemeanthidine chloride, and ellipticine are some of the alkaloids with promising anticancer effects mediated by targeting MAPK, FAS and

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Akt [334-337].

5.1.4 Sulfur-containing plant secondary metabolites As secondary sulfur-containing compounds, glucosinolates and alliinins are two major classes of compounds found in relatively high levels in plants. The glucosinolates are a wellknown category of secondary plant metabolites described via having an S-β-d-glucopyrano unit a 36

numerically contiguous to an O-sulfated (Z)-thiohydroximate function. Glucosinolates are anionic natural products observed in mustards, cabbages, and related plants, mostly the cabbage order, families of Brassicales [203]. Myrosinase is considered as a cellular defense-related enzyme capable of hydrolyzing glucosinolates structures into variant compounds, some of which are toxic. More recently, due to the therapeutic impact of glucosinolates and related products resulting from their degradation on human health, they have attracted considerable attention. In

of

addition to their defensive role in plants against pests and pathogens, various glucosinolates and

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their degradation products play essential roles in the treatment of cancer, cardiovascular and neurological diseases [338, 339].

-p

As a glucosinolate, sinigrin suppressed the proliferation of HepG2 cells in vitro and was

re

capable of preventing liver toxicity and restoring liver functions in carcinogen-induced hepatotoxicity in vivo [208] (Table 4). Moringin was obtained from Moringa oleifera seeds and

lP

can be produced via myrosinase-catalyzed hydrolysis of the precursor glucomoringin. It could successfully inhibit the growth of human neuroblastoma cells and induced the apoptosis of H-

ur na

SY5Y cell line via interfering with the NF-κB and apoptosis-related factors [209]. In a similar study, the beneficial effect of moringin in combination with avenanthramide was investigated, and the results emphasized that this combination therapy induced the extrinsic and intrinsic apoptosis, suppressed the proliferation of Hep3B Cell line, and increased the levels of

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intracellular ROS and caspase-9, caspase-8, caspase-2, and caspase-3 [210]. Also, it was reported that moringin inhibited IL-3-induced STAT5 signaling in HeLa cell line [211]. Glucomoringin is an uncommon member of the glucosinolate category. The result of the effect of the myrosinase enzyme on the glucomoringin is isothiocyanate formation, which can play a key role against tumors. Rajan et al. [212] investigated the in vitro anticancer activity of glucomoringin

37

isothiocyanate in CCF-STTG1 human malignant astrocytoma cells. Moringin derived from myrosinase hydrolysis of glucomoringin showed the suitable antitumor efficacy via inducing apoptosis and oxidative stress in vitro. Besides, the rich extract of glucomoringin-isothiocyanate facilitated the apoptotic process and prevented the proliferation of PC-3 human prostate adenocarcinoma cells [213]. As mentioned earlier, isothiocyanate and sulforaphane are some of

of

the important chemical structures that are produced when the enzyme myrosinase transforms glucosinolate into other compounds. Inhibiting COX-2, NF-B, microsomal prostaglandin E

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synthase-1 expression, increasing ROS, and targeting FAK/Akt and FAK/ERK signaling pathways are the proposed anticancer mechanisms of isothiocyanate and sulforaphane against

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5.1.5 Miscellaneous compounds

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various cancer cell lines [214-216].

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Several miscellaneous compounds have also shown promising anticancer effects. Methyl protodioscin, bixin, rapanone, oxyresveratrol, and indole-3-carbinol have been found to possess

ur na

promising anticancer effects against various cancer cell lines [340-344]. 3,3′-diindolylmethane is a bioactive substance obtained from the digestion of indole-3-carbinol, which exists in cruciferous vegetables, such as brussels sprouts, cabbage, broccoli, and kale. Recently, the in

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vitro anticancer activity of 3,3’-diindolylmethane on SMMC-7721 and HepG2 cells has been found to be mediated through activation of p38-MAPK [340] (Table 5). Moreover, it exhibited an anticarcinogenic effect against human colorectal adenocarcinoma cell lines via interfering with endoplasmic reticulum stress and down-regulating cyclin D1 [341]. Additionally, the amelioration of Akt, ERK1/2, STAT3 signaling, and COX1/2 are the proposed anticancer mechanisms of 3,3′-diindolylmethane in colon/ovarian cancer cells [342, 343]. Shikonin, a

38

naphthoquinone isolated from the roots of the Lithospermum erythrorhizon, exhibited several therapeutic effects, such as antimicrobial, antitumor, anti-inflammatory and anti-human immunodeficiency virus (HIV) activities. Shikonin exerted its anticancer activity through downregulation of EGFR/p-ERK and the suppression of β-catenin signaling in MCF-7, SK-BR-3, and breast cancer cells [344, 345]. Besides, interfering with Akt/mTOR, ROS/ERK and HIF-1α signaling pathways are some of the suggested anticancer effects of shikonin in the prostate, lung,

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and human colon cancer cell lines [346-348]. Amygdalin is a cyanogenic glycoside present in the

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leaves and seeds of variant species of Rosaceae, such as loquat, plum, apricot, and peach. Previous studies showed that amygdaline exhibited several beneficial effects, including

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antiasthmatic, antinociception, antihyperglycemic, immune-suppressive and antitumor activity

re

[349]. From the anticancer point of view, amygdalin inhibited the growth and postponed progression of the cell cycle in vitro [350], through enhancing the Bax/Bcl-2 ratio in the SK-BR-

lP

3 [351] and HeLa cell lines [352]. Pinitol, a polyol compound, has been shown to possess potential anticancer effects through targeting death receptors and related downstream signaling

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mediators involved in inflammation (NF-B and COX-2), proliferation (c-myc and cyclin D1), invasion (MMP-9), angiogenesis (VEGF) and apoptosis (Bax and Bcl-2), thereby combat cancer [353]. In addition, methyl protodioscin, bixin, rapanone, oxyresveratrol, and indole-3-carbinol are some of the other compounds with promising anticancer effects and known mechanism of

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action against variant cancer cell lines [354-358]. Interstingly, targeting CXCR4, an upstream inflammatory receptor, by another natural compound butein has also been a critical approach of suppressing breast and pancreatic cancer [359].

39

5.2. Clinical studies As major strategies in cancer treatment, chemotherapy, radiotherapy, and surgery have shown severe side effects and progressive resistance in clinical studies. Besides, due to the complexity of pathophysiological mechanisms of cancer metabolism, evaluating efficient phytochemicals is of great importance. So, investigating the phytochemicals in cancer treatment is critically needed. Nevertheless, most of the reported studies are of preclinical nature. While

of

the phytochemicals are mostly tested on early-stage cancers, few of them are being evaluated in

ro

patients with advanced cancer. Recent reports of appropriate completed/ongoing clinical trials have revealed promising results of phytochemicals in cancer, and some of these studies are

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discussed here.

re

Due to the wide colonic distribution of curcumin and its preferential distribution into the colonic mucosa compared to other tissues, a number of preliminary clinical studies focused on

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its probable anticancer effects in colorectal cancer models [360]. Building upon previous preclinical studies, curcumin has shown powerful anticancer effects in pancreatic and colorectal

ur na

cancer in several clinical trials. It reduced the expression of some cross-linked pathways in cancer metabolism, including NF-κB, COX-2, and p-STAT3, in peripheral blood mononuclear cells of patients with pancreatic cancer [361]. Curcumin also decreased the activity of glutathione S-transferase in colorectal cancer [362]. Curcumin was also found to modulate the

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expression of various transcription and growth factors (e.g., PDGFR, EGFR, and FGF), as upstream regulators of cancer metabolism in clinical studies [363]. Besides, the inhibition of ERK, MAPK, protein kinase C and PI3K was also considered as other anticancer mechanisms of curcumin [364]. Besides, in some studies, up to 8 g per day of curcumin was considered to be safe in humans [361, 362, 365]. In a clinical study, six months of co-administration of curcumin

40

and quercetin also decreased the numbers and sizes of polyps in familial adenomatous polyposis without any substantial side effects [366]. In several other clinical trials, curcumin is being tested for the prevention and treatment of various human cancers, including colon (NCT00973869, NCT00027495, NCT00295035), rectal, (NCT02321293),

breast

oral,

(NCT01740323),

head and

pancreas

neck (NCT01160302),

(NCT00192842,

lung

NCT00094445,

NCT00486460) and prostate (NCT03211104, NCT02724618, NCT02138955) cancers as well as

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osteosarcoma (NCT00689195), glioblastoma (NCT01712542), chronic lymphocytic leukemia

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and small lymphocytic lymphoma (NCT02100423) [367, 368].

Some other phenolic compounds (e.g., tea polyphenols) have also played an important role

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in cancer prevention. In this line, tea polyphenols reduced the progression rate of premalignant

re

oral lesions during a randomized, double-blinded clinical trial [369]. In a randomized, controlled pilot trial, another polyphenol, epigallocatechin gallate (EGCG), is already used in the prevention

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of colorectal cancer progression in patients with curative resections (NCT02891538). From the cancer metabolism point of view, EGCG inhibited glucose uptake by targeting GLUT, and also

ur na

decreased the lactate production, thereby reduced cancer progression [370]. In a non-randomized open-label clinical trial silibinin, another phenolic compound showed a promising anticancer effect against prostate cancer (NCT00487721). Genistein has also shown encouraging anticancer effects in several clinical trials of breast cancer (NCT00244933), prostate cancer (NCT00058266

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and NCT01126879), lung cancer, solid tumors (NCT01628471), metastatic melanoma and kidney cancer (NCT00276835), recurrent acute lymphoblastic leukemia, and non-Hodgkin's lymphoma (NCT00004858) by the inhibition of NF-κB and Akt signaling pathway, cross-linked with cancer metabolism [371]. In phase I/II open-label clinical trial, genistein alone or in

41

combination with decitabine was used in pediatric relapsed or refractory malignancies (NCT02499861). Resveratrol, another phenolic compound with fewer unwanted side effects [372], possess promising anticancer effects in the colon (NCT00256334), gastrointestinal (NCT01476592), breast [373], prostate [374] and several other cancer types through targeting multiple-steps involved in cancer progression [375, 376]. In two studies, the mechanistic effects of resveratrol

of

on apoptosis and Notch-1 signaling were assessed (NCT00256334 and NCT01476592). The

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antiproliferative effects of resveratrol against breast cancer [373], in addition to its inhibitory effects on methylation of four cancer genes (p16, RASSF-1α, APC, and CCND2), were also

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confirmed [377]. Brown et al. [378] investigated the ameliorating role of resveratrol on IGF-

re

binding protein 3 and insulin-like growth factor as two factors associated with tumor formation and metastasis in different cancer types. The regulatory effect of resveratrol on DHEA was

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shown in a 4-month randomized trial in middle-aged men suffering from the metabolic syndrome [374]. As previously mentioned, resveratrol exerts its anticancer effects by affecting PI3K/Akt,

ur na

TRAF/NF-κB, TRAIL, TGFβ1/SMAD, caspase, and SREBP1. In another study, the effect of resveratrol on plasma cytochrome P450 enzyme was evaluated and the inhibitory effect of resveratrol on CYP3A4, CYP2D6, and CYP2C9 was shown [379], which must be considered in co-administration with other anticancer agents. From another mechanistic point of view,

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resveratrol could promote the immune system in healthy individuals, through upregulating NKG2D in NK cells, thereby elevated the elimination rate of cancer cells [380]. These results were in line with previous preclinical studies [381, 382]. In another randomized open-label clinical trial, andrographolide showed anticancer effects either alone or in combination with capecitabine (NCT01993472). The activation of TRAIL and

42

caspase-8, while the inhibition of inflammatory factors (e.g., TNF-α, NF-κB, and COX-2) and angiogenic factor (VEGF), have been considered as main anticancer mechanisms of andrographolide [383]. Additionally, berberine also exerted anticancer effects in an open-label clinical trial (NCT03486496). Previously, the modulation of glycolysis, mitochondrial oxidative phosphorylation [322], AMPK, mTOR, and HIF-1α was shown as main anticancer mechanisms of berberine [318-320].

of

Of the other plant-derived secondary metabolites, betulinic acid showed a promising

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anticancer effect in clinical studies [363, 384]. The underlying mechanisms of action of betulinic acid include induction of the mitochondrial apoptotic pathways through down-regulation of

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Bcl-2, up-regulation of pro-apoptotic cytochrome c and caspases, increase in p53 and reduction

re

of mediators involved in the NF-B pathway [16, 385-387]. Additionally, betulinic acid attenuated STAT3/HIF-1α/VEGF signaling thereby exhibiting antiangiogenic responses in

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cancer. In order to inhibit the progression of liver cancer, betulinic acid exerted a synergistic effect with TRAIL [388]. These mechanisms of betulinic acid seem to contribute to its beneficial

ur na

effects against various cancer types, including cancers of the prostate, bladder, stomach, pancreas, cervix, ovary, colorectum, liver, lung, breast, skin, head and neck as well as chronic myeloid leukemia [16, 389]. Overall, based on available clinical results, the plant-derived natural

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products represent promising anticancer agents.

6. Conclusion and perspective Cancer metabolism has been now an area of extensive attention. The cancer metabolism has

recently been considered as emerging hallmarks. As critical goals in cancer therapy, altered metabolic pathways could be the promising target to combat cancer cells. Targeting these

43

metabolic dysregulations and related signaling pathways hold promise as a new strategy to develop novel anticancer agents. Despite the importance of targeted therapy, most cancers could not be diminished solely with single-target therapies. Besides, the complex pathophysiology of cancer metabolism, as well as the interconnections between signaling pathways and cancer metabolic pathways raise the need to find novel multi-targeted therapeutic agents [13]. Natural entities have shown the

of

potential to be promising multi-targeted agents, targeting altered signaling pathways in cancer

ro

metabolism with fewer side effects. These effects have introduced plant-derived secondary metabolites as promising compounds for cancer prevention and therapy. Plant secondary

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metabolites modulate the metabolism of carbohydrates, proteins, and lipids as well as epigenetic

re

changes in cancer. These compounds also target several dysregulated cross-linked signaling pathways/mediators involved in cell overproliferation. Therefore, plant secondary metabolites

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affect dysregulated metabolism to hinder carcinogenesis.

In spite of their effectiveness, plant secondary metabolites often suffer from instability, poor

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bioavailability, low solubility, and low selectivity, which limit their therapeutic uses in cancer. Some clinical trials showed that various phytochemicals are absorbed with low efficiency. Additionally, chemical degradation and rapid metabolism and clearance of phytochemicals cause their low plasma concentration. The dawn of nanotechnology has favorably overcome these

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pharmacokinetic limitations through enhancing bioavailability, cellular uptake, targeting, specificity and efficacy of anticancer secondary metabolites. Accordingly, polymeric/metallic nanoparticles, liposome, micelle, and solid-lipid nanoparticles have played critical roles in improving the anticancer effects of plant secondary metabolites [390-392].

44

This review underscores the importance of targeting the alterations in cancer metabolism by multi-targeted secondary metabolites to combat cancer. A future area of research should identify more precise signaling pathways of cancer metabolism, develop novel formulation and drug delivery methods and focus on well-controlled clinical trials to evaluate phytochemicals with reduced cost, toxicity and drug-resistance in the prevention, treatment, and management of

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cancer.

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Acknowledgments

Adobe Photoshop® software (version 2015, Adobe Inc., San Jose, CA) was used to prepare

Declaration of Competing Interest

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mechanistic figures.

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The authors declare no conflicts of interest.

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Legends to figures:

Fig. 1. Major dysregulated pathways in cancer metabolism and key targets of plant secondary metabolites.

2-hG:

2-hydroxyglutarate,

6-PG:

6-Phosphogluconate,

6-PGLDH:

6-

phosphogluconate dehydrogenase, ACC: Acetyl-CoA carboxylase, ACL: ATP citrate lyase, αkG: α-ketoglutarate, F: fructose, 3PG: 3-phosphogluconate, Fum: fumarate, G: glucose, G-6P:

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Glucose 6-phosphate, G6PD: Glucose 6-phosphate dehydrogenase, GAPDH: glyceraldehyde-3phosphate dehydrogenase, GDH: glutamate dehydrogenase, GLS: glutamate synthase, GLUT:

ro

glucose transporter, GSH: glutathione, GSS: glutamylcysteine synthetase, HDACs: histone

-p

deacetylases, IDH: isocitrate dehydrogenase, LDH: lactate dehydrogenase, LDH: lactate dehydrogenase, LSD: lysine-specific demethylases, MCT: monocarboxylate transporter, MDH:

re

malate dehydrogenase, PDH: pyruvate dehydrogenase, PDK: pyruvate dehydrogenase kinase,

lP

PEP: phosphoenolpyruvate, PGK: phosphoglycerate kinase, Suc: succinate, TCA: tricarboxylic acid cycle.

ur na

Fig. 2. Excessive production of lactate and its role in immune suppression and drug resistance. DC: dendritic cells, MDSC: myeloid-derived suppressor cells, NK cell: natural killer cell, iNOS:

Jo

inducible nitric oxide synthases, NF-κB: nuclear factor-B, PI3K: phosphoinositide 3-kinase.

Fig. 3. Main dysregulated cross-linked signaling pathways and key targets of plant secondary metabolites in cancer metabolism. Akt: protein kinase B, EGFR: epidermal growth factor, ERK: extracellular-signal-regulated kinase, GFR: insulin-like growth factor, GSH: glutathione, GSK: glycogen synthase kinase, GST: glutathione S-transferases, HO-1α: hem oxygenase 1α, HER2: human epidermal growth factor receptor 2, HIF-1α: hypoxia-inducible factor-1α, IL: interleukin,

68

JNK: c-Jun N-terminal kinases, MAPK: mitogen-activated protein kinase, mTOR: mammalian target of rapamycin, NF-κB: nuclear factor-B , NQO-1: NAD(P)H dehydrogenase (quinone 1), Nrf2: nuclear factor erythroid-2-related factor 2, PI3K: phosphoinositide 3-kinases, PTEN: phosphatase and tensin homolog, SOD: superoxide dismutase, SREBP: sterol regulatory

of

element-binding proteins, VEGF: vascular endothelial growth factor.

Fig. 4. Death receptor, TNF-αR, and IL-6R cross-linked signaling pathways and key targets of

ro

plant secondary metabolites in cancer metabolism. AIF: apoptosis-inducing factor, IL: interleukin, COX: cyclooxygenase, JAK: Janus kinase, STAT: signal transducer and activator of

-p

transcription, PGC-1α: peroxisome proliferator-activated receptor γ coactivator 1-α, TNF-α:

lP

necrosis factor receptor-associated factor

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tumor necrosis factor-α, TRADD: TNFR1-associated death domain protein, TRAF: tumor

ur na

Fig. 5. Chemical structures of selected phenolic compounds (A) and terpenoids (B).

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Fig. 6. Chemical structures of selected alkaloids (A), and sulfur-containing compounds (B).

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Table 1. The preclinical evidence of phenolic compounds and related therapeutic targets in regulating cancer metabolism. Types of study

Cell line(s)/cancer model(s)

Mechanism of action/metabolic effects

Curcumin

In vitro

Human leukemic cells (U937 and K562)

In vitro and in vivo

Head and neck squamous carcinoma cells (HEp-2, SCC-15 and FaDu) Xenograft nude mouse model

In vitro and in vivo

Human urothelial carcinoma cell (UMUC2 and T24) Rat urothelial tumor model Human liver cancer cell (HepG2) Xenograft nude mice model

ro

Compound

Jo

In vitro and in vivo

[218] ↑Apoptosis via an IFIT2-dependent pathway ↓Bcl-2 ↑Cleaved PARP and cleaved caspase-3 [219] ↑Apoptosis G2/M cell cycle ↓Angiogenesis ↑ATM expression ↓HIF-1α expression ↑ATM/Chk2/p53 signal pathway ↓IGF2 and IGF2-mediated PI3K/Akt/mTOR signaling [220] pathway

-p

re

In vitro and in vivo

In vitro

lP

ur na

In vitro and in vivo

References

Gastric carcinoma cell (AGS, SNU-1 and SNU-5) Xenograft nude mice model Human colon cancer cells (SW620 and SW480) Murine lymphocytic leukemia cell (L1210) Murine breast tumor cell (4T1) Murine melanoma cell (B16) Murine colon tumor cell (CT26) B16 xenograft mouse model 76

↑Apoptosis ↑ROS ↑p53 ↑Akt ↓Wnt/β-catenin signaling pathway ↓p-LRP6, Wnt3a, c-Myc, LRP6, p-β-catenin and βcatenin ↑AMPK signaling pathways ↓mTORC1 signaling pathways ↓ATP-synthase activity

[221]

[222]

[223] [224]

In vitro

Human breast cancer cells (SKBR3)

In vitro

Human gastric adenocarcinoma cell (AGS)

In vitro and in vivo

Human chondrosarcoma cell (JJ012) Chondrosarcoma xenograft mouse model

In vitro and in vivo

Human liver cancer cells (Hep3B, MHCC97-L and MHCC97-H) Xenograft mouse model Human colorectal carcinoma cells (HCT116)

In vitro and in vivo

In vitro

re

lP

ur na

In vitro

↑BMP7 ↓PI3K/Akt signaling ↓p-PTEN ↑Apoptosis ↑Bax and caspase-8 ↓Pro-caspase-3 and pro-caspase-9 ↓PI3K/Akt ↓VEGF ↓Cell proliferation ↓Cell migration ↓EMT ↓TRAF6/NF-κB/SLUG axis

[231]

of

Human breast (MCF-7), lung (H1299), cervix (HeLa) and prostate (PC-3) cancer cells

[225]

ro

In vitro

↑Polyamine catabolic enzymes (SSAT and PAO) ↓STAT-1, STAT-5, and STAT-3 ↓Bcl-2 ↑Bax ↓Lactate production and glucose uptake (Warburg effect) ↓PKM2 expression ↓mTOR/HIF-1α axis ↓FAS expression and mRNA level ↓FAS activity ↓Biosynthesis of polyamine and intracellular polyamine pools ↑Catabolism of spermine via spermine oxidase ↓Cell viability ↑Apoptosis ↑Sirtuin-1 signaling ↑SIRT1 ↓NF-κB signaling ↓HGF-c-Met signaling pathway

-p

Human breast cancer cells (MCF-7, MDA-MB-231and MDA-MB-453)

Jo

Resveratrol

In vitro

Human liver cancer cell (HepG2) Xenograft nude mouse model

Human prostate cancer cells (DU-145 and PC-3)

77

[226]

[227] [228]

[229]

[230]

[232]

[233]

In vitro

Human prostate cancer cells (LNCaP)

In vitro

Human lung carcinoma cells (A549, NCI H460 and NCI H23)

In vitro and in vivo

Human pancreatic cancer cells (MiaPaCa‐2 and Panc-1) KPC mouse model Colon cancer cells (Caco2 and HTC116) Breast cancer cell (MCF-7) Human ovarian cancer cells (SKOV3 and A2780) Xenograft nude mouse model Human lung cancer cells (H460, H1650 and HCC827) Xenograft mouse model Breast cancer cells (MDA-MB231 and MCF-7) Xenograft nude mouse model Human breast cancer cells (SKBR-3)

In vitro and in vivo

In vitro and in vivo

Jo

In vitro

Quercetin

re

ur na

In vitro and in vivo

lP

In vitro

In vitro and in vivo

↓MMP-9, cyclin D1, MMP-2, and c-Myc ↓Sox2 ↓Activation of Akt and STAT3 ↓AR and CXCR4

[234]

↑p53 and p21 ↑Caspases cascade ↓Smad activators 2 and 4 G1 cell cycle arrest ↑Sensitivity of gemcitabine ↓Lipid synthesis through SREBP1

[236]

↑CamKKB/AMPK signaling pathway ↓Pentose phosphate activity ↑ATP production ↓Glycolysis ↑AMPK/mTOR signaling pathway

[238]

↓Glucose metabolism ↓HK2 expression ↓Akt signaling pathway ↓Lipogenesis ↓FAS mRNA and protein levels

[240]

↓FAS protein level ↓FAS expression ↓Her2 ↑Ets factor and PEA3 expression ↑PI3K/Akt/mTOR signaling ↓p-PI3K and p-Akt ↓VEGF and VEGFR2 protein

[242]

ro

Human breast cancer cells (MDA-MB231 and MCF-7)

-p

In vitro

of

↓NF-κB

Human prostate cancer cells (PC-3 and LNCaP) 78

[235]

[237]

[239]

[241]

[245]

In vitro and in vivo

Breast cancer cells (MDA-MB-157, MDA-MB-231) Xenograft albino mouse model

In vitro

Human liver cancer cells (TFK-1, HepG2, HuH7 and Hep3B2.1–7)

In vitro

Jo

In vitro and in vivo

Naringin

In vitro

In vitro

lP

In vitro and in vivo

ur na

Naringenin

↑Apoptosis via the MAPKs pathway ↓β-catenin, E-cadherin, N-cadherin and snail ↓Expression of MMPs and TIMPs ↓Activity of MMP-2 and MMP-9 ↓FAS protein level ↓FASN and β-catenin ↓Bcl-2 ↑Caspase-3 activation ↓GLUT1 cytoplasmic fraction ↑GLUT1 membrane expression ↓18F-FDG uptake ↑ROS generation and induction apoptosis via ROS ↑p-Akt ↑Activation of the MAPK pathways G0/G1 phase ↑Caspase-3, caspase-7 and caspase-9 ↑DNA breakdown ↑Bax ↓MMP-2 and caspase-9 ↑TIMP 1/2 ↓p-p38 ↑Apoptosis via influencing in FAK/Bads pathway ↓FAK activity and FAK/MMPs pathway

[249]

of

[246]

ro

In vitro and in vivo

↓Bcl-2 ↑Bax ↑p-p38, p-ERK1/2, and p-JNK ↓Activation of Snail-dependent Akt ↑Maspin ↓ADAM9 ↑MAPK pathway ↓AKT/mTOR pathway

-p

In vitro and in vivo

re

In vitro and in vivo

Xenograft nude mouse model Human melanoma cells (A375SM and A375P) Xenograft nude mouse model NSCLC cells (H1975, A549 and HCC827) Orthotopic mouse model Human liver cancer cells (SMMC7721 and HepG2) Xenograft mouse model Mouse colon carcinoma cells (MC38, CT26 and CCD-18Co) Xenograft nude mouse model

Human placental choriocarcinoma cells (JEG-3 and JAR) Human breast cancer cells (MCF-10A and MDA-MB-231) Female Wistar rat model of breast cancer Human glioblastomas cell (U251)

Human glioblastomas cells (U251 and U87 MG) 79

[247]

[248]

[250]

[251]

[252]

[253]

[254]

[255]

In vitro and in vivo

Daidzein

In vitro and in vivo

Apigenin

In vitro

Human colon cancer cells (HCT116, HT29 and DLD1)

Pelargonidin In vitro

Human liver cancer cell (HepG2-C8) Mouse epidermal cell (JB6)

Malvidin

In vitro

Human colorectal cancer cells (HCT1161)

Gallic acid

In vitro

Morin & esculetin

In vivo

re

lP

ur na

Jo In vitro

↑Caspase-dependent apoptosis ↑Cleaved caspase-8 ↑Death receptor 5 ↓ Nrf2/ARE signaling pathway ↓ERK1/2

[256]

↑Apoptosis ↓MMP-9 and MMP-2 G2/M cell cycle ↓Raf/MEK/ERK cascade ↓Cdc2, pcdc2, cdc25c, pcdc25c, and cyclin B1 ↓Activity and level of PKM2 protein ↓Lactate production and glucose uptake ↓β-catenin/c-Myc/PTBP1 signal pathway ↓DNA methylation of Nrf2 promoter ↓TPA-induced cell transformation ↓DNMTs and HDACs ↑Apoptosis G2/M cell cycle arrest ↑p21WAFI ↑GAPDH, PK, glucokinase, aldolase and α-enolase levels ↑Cleaved forms of PARP-1, caspase-9 and caspase-3 ↓ Bcl-2 and Bcl-xL ↓c-Myc-induced energy metabolism ↓Glutaminolysis and glycolysis ↓PCNA and AgNORs ↓c-Myc, c-jun and c-fos ↓GLUT1 and HK2 ↓PKM2 and LDHA ↓Cyclin D1, COX-2, MMP-9 and NF-κB

[258]

of

Chrysin

Morin

Human oral cancer cells (YD15 and HSC-4, Ca9.22) Xenograft nude mouse model Human glioblastomas cells (T98, U251 and U87) Xenografts nude mouse model Human ovarian cancer cell (SKOV3) Xenograft nude mouse model

ro

In vitro and in vivo

[257]

-p

Silymarin

Mouse melanoma cells (B16F10)

Male albino Wistar rats model of colon cancer

Human lung carcinoma cell (A549) Human cervical cancer cell (HeLa) 80

[259]

[260]

[261]

[262]

[263]

[264]

Jo

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lP

re

-p

ro

of

↑: Increase or up-regulation, ↓: decrease or down-regulation, : blockade, ¹⁸ F-FDG: fludeoxyglucose, AgNOR: argyrophilic nucleolar antigen, Akt: protein kinase B, AMPK: AMP-activated protein kinase, AR: androgen receptor, ARE: antioxidant response element, ATM: ataxiatelangiectasia mutated, Bcl-2: B-cell lymphoma 2, Bcl-xL: B-cell lymphoma-extra-large, BMP7: bone morphogenetic protein 7, Chk2: checkpoint kinase 2, CXCR4: C-X-C chemokine receptor type 4, DNMTs: DNA methyltransferases, EMT: epithelial-mesenchymal transition, ERK1/2: extracellular signal-regulated protein kinase, FAK: focal adhesion kinase, FAS: fatty acid synthase, FAS: fatty acid synthase, GAPDH: gyceraldehyde 3-phosphate dehydrogenase, GLUT1: glucose transporter 1, HDACs: histone deacetylases, HIF-1α: hypoxia-inducible factor 1α, HK2: Hexokinase 2, IFIT2: interferon-induced protein with tetratricopeptide repeats 2, JNK: c-Jun NH2-terminal kinase, LDHA: lactate dehydrogenase A, MAPKs: mitogen-activated protein kinases, MMPs: matrix metalloproteinases, mTOR: mammalian target of rapamycin, NF-E2: nuclear factor erythroid 2, NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cell, Nrf2: nuclear factor erythroid 2-related factor 2, NSCLC: Non-small cell lung cancer, OXPHOS: oxidative phosphorylation, PARP: poly ADP ribose polymerase, PCNA: proliferating cell nuclear antigen, PI3K: phosphatidylinositol 3-kinases, PKB: protein kinase B, PKM2: pyruvate kinase M2, PTEN: phosphatase and tensin homolog, ROS: reactive oxygen species, SIRT1: Sirtuin-1, SREBP-1: sterol regulatory element-binding protein 1, STAT: signal transducer and activator of transcription, TIMPs: tissue inhibitor of metalloproteinases, TPA: 12-O-tetradecanoylphorbol-13-acetate, VEGF: vascular endothelial growth factor, VEGFR2: vascular endothelial growth factor receptor 2.

81

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Table 2. The preclinical evidence of terpenoids and related therapeutic targets in regulating cancer metabolism.

Monoterpene

Monoterpene

Human prostate cancer cells (PC-3) In vitro and Human lung cancer cells in vivo (A549 and PC-9) Xenograft athymic nude mouse model In vitro Human colon cancer cells (HCT116 and LoVo)

In vitro

Human gastric adenocarcinoma cells (AGS)

Monoterpene

In vitro

Monoterpene

In vitro

Human breast cancer cells (MCF-7) Human liver cancer cells (HepG2)

ur na

Monoterpene

Jo

Geraniol

Isobutyroylplenolin & arnicolide D

Mechanism of action/metabolic References effects [268] ↓IL6 gene expression ↓pSTAT3, pERK1/2 and pAkt [269] ↑ROS generation

ro

Monoterpene

Cell line(s)/cancer model(s)

-p

Carvacrol

Types of study In vitro

re

Classification

lP

Compound

Monoterpene

In vitro

Human prostate cancer cells (PC-3)

Sesquiterpene

In vitro

Human colon carcinoma cells (HT-29)

82

↓Proliferation and migration ↓Expression of MMP-2 and MMP-9 G2/M cell cycle arrest ↓Expression of cyclin B1 ↑Apoptosis ↓Expression of Bcl-2 ↑Bax and c-Jun N-terminal kinase ↓Proliferation ↑Apoptosis ↑ROS generation G2/M cell cycle arrest ↓CDK 2 ↓Mevalonate pathway ↓Biosynthesis of phosphatidylcholine ↓HMGCR ↑p-ACC protein level ↓Akt/mTOR signaling ↑AMPK signaling ↓Proliferation ↑Apoptosis G1 cell cycle

[270]

[271]

[272] [273]

[274]

[276]

DMAMCL

Sesquiterpene

Triptolide

Diterpenoid

of

Sesquiterpene

ro

Cacalol

-p

Sesquiterpene

[277]

[278]

[279]

ur na

lP

re

Zerumbone

↑ROS ↓NF-κB In vivo Mouse model of colorectal ↓Proliferation and lung caner ↑Apoptosis ↓HO-1 ↓NF-B In vitro and Human breast cancer cells ↑caspase-3 and DAPK2 in vivo (MCF-7 and MDA-MB-231) ↓Expression of the FAS gene Xenograft nude mouse ↓Akt-SREBP signaling pathway model In vitro Human malignant glioma ↑Intracellular PK activity cell lines (U118MG, ↓Lactate and glucose-6-phosphate U251MG, SF126, SHG-44 ↓Anaerobic metabolism and U87MG) ↓Sedoheptulose-7-phosphate ↓Glycerol-3-phosphate In vitro and Murine breast tumor cells ↑Apoptosis in vivo (4T1) Human breast cancer cells (MCF-7) Human liver cancer cells (HepG2) Xenograft BALB/c nude mouse model In vitro and Human esophageal G1/S cell cycle in vivo squamous carcinoma cells ↑Apoptosis via cyclin D1-CDK4/6 (Eca 109, KYSE180 and regulation KYSE150) ↑Caspases activation Xenograft mouse model In vitro Human breast cancer cells ↓XRCC1 and PARP1 (MDA-MB-231 and BT549) S phase cell cycle ↑DNA breaks ↓RAD51 In vitro NSCLC cells (H1299 and ↑Apoptosis

Jo

Diterpenoid

Diterpenoid

Diterpenoid

83

[281]

[282]

[283]

[284]

↓p-mTOR, p-Akt, and p-p70S6K ↑Apoptosis ↑GSH depletion ↓Glucose utilization ↓HKII expression ↓ATP levels ↓Nrf2 ↓c-Myc expression Nrf2/ARE activity

In vitro and NSCLC cells (A549) in vivo Human liver cancer cells (HepG2) Lewis lung cancer cells (3LL) Xenograft nude mouse model In vitro Human prostate cancer cells (PC-3 and DU-145)

[285]

ur na

Diterpenoid

lP

re

Diterpenoid

-p

ro

of

NCI-H460)

Triptolide

Jo

Diterpenoid

Carnosic Acid

Diterpenoid

Diterpene

In vitro

Human colon cancer cells (HT29 and SW480 )

In vitro and Human mesangial cells in vivo (HMC) Sprague-Dawley rats In vitro Mouse melanoma cells (B16F10) 84

↓Proliferation ↓Migration and invasion ↓Expression Cav-1 ↓CD147 activities ↓MMPs activities ↓Proliferation G1 phase cell cycle ↓GABPα expression ↓p-ERK and p-Akt ↓LEF/TCF ↓CDKN2C, CDK7, CDC23, SMAD3, FOS, CASP3, ATP5E and COX11 ↑Autophagy ↓miR-141-3p levels ↓miR-141-3p/PTEN/Akt/mTOR ↓MMP-9, TIMP-1 and VCAM-1 ↑TIMP-2

[286]

[287]

[288]

[289]

↓p-Src, p-Akt and p-FAK

ro

of

Mouse colon adenocarcinoma cells (CT26) Lewis lung carcinoma cells (LLC) Human colorectal cancer cell (HT-29)

Diterpene

In vitro

Andrographolide

Diterpene

In vitro

Geranylgeranoic acid

Diterpene

In vitro

Oridonin

Diterpene

In vitro

Human colon cancer cells (SW620 and SW480)

Diterpene

In vitro

Human colon cancer cells (SW620 and SW480)

Diterpene

In vitro

Diterpene

In vitro

Uveal melanoma cells (OCM-1 and MUM2B) Human lung cancer cells (A549)

re

Immortal AML cells (MV411)

Human liver cancer cells (HuH-7)

lP

ur na

Jo Pseudolaric acid B

-p

Kahweol

85

↑Caspase-3 ↓Bcl-2 and p-Akt ↓HSP70 ↓Fatty acid synthesis ↓Protein synthesis ↓FAS and ACC1 ↑STIM1 ↓Iron uptake ↓FLT3 signaling ↓Fructose 1,6-diphosphate ↑Fructose 6-phosphate ↑Spermine ↓Spermidine ↑SCO2 and TIGAR ↑ATP generation ↓GLUT1, MCT1 mRNA and protein level ↓Glucose uptake ↓Lactate export ↓FAS mRNA level ↓FAS protein level ↓Stearic acid and palmitic acid ↓SREBP1 mRNA ↓FAS protein level ↑Bim expression ↑GLUT1 protein level ↑Glucose uptake and lactate production

[290]

[291]

[292]

[293]

[294]

[295] [296]

of

In vitro and Human prostate cancer cells in vivo (PC-3)

Triterpenoid

In vitro

Triterpenoid

In vitro

Triterpenoid

In vitro

Plectranthoic acid

Triterpenoid

In vitro

Jo

Tubeimoside-1

Pachymic acid

Triterpenoid

-p

Human liver cancer cells (HepG2) Human breast cancer cells (MCF-7, SK-BR-3 and MDA-MB-231)

re

ur na

Triterpenoid

ro

Triterpenoid

Human prostate cancer cells (DU145 and LNCaP) Transgenic mouse model of prostate adenocarcinoma (TRAMP mice) Human breast cancer cells (MCF-7 and T47D)

lP

Ursolic acid

↑ATP generation ↑HK-2 protein level ↑Cleaved PARP ↑Caspase-3 and caspase-9 ↓Bcl-XL, Bcl-2 and Mcl-1 ↑Bax ↓Proliferation G2/M phase cell cycle G0/G1 phase cell cycle ↓Akt signaling ↓ATP generation ↓HK2 and PKM2 ↓Lactate production ↓p-ERK1/2 ↓CXCR4/CXCL12 signaling axis ↓Expression of CXCR4 ↓NF-κB activation

In vitro

Human prostate cancer cells (NB26, DU-145, PC-3 and CW22Rν1) Human melanoma cells (A375) Human breast cancer cells (SK-BR-3)

86

[297]

[298] [299]

[300]

↓Akt activity ↓Phosphorylation of Akt ↓mTOR activity ↑LC3-II amount and GFP-LC3 ↓Mcl-1, Bcl-xl, and Bcl-2 G0/G1 phase cell cycle ↓mTOR/S6K signaling ↑AMPK ↑p21/CIP1 and p27/KIP1

[301]

↓ PKM2 ↓HK2 activity ↓Glucose uptake and lactate production

[303]

[302]

Oleanolic acid

Triterpenoid

of

Triterpenoid

ro

Avicin G

-p

Triterpenoid

[304]

[305]

[306]

ur na

Triterpenoid

lP

re

Cucurbitane

↑Mitochondrial dysfunction ↓ATP ↑ROS generation In vitro Human breast cancer cells ↑Autophagy (MCF-7 and MDA-MB-231) ↓mTOR ↑PPAR 𝛾 In vitro and Human leukemia cells ↓Tumor cells energy metabolism in vivo (Jurkat cells) ↓ATP ↑VDAC closure In vitro Human breast cancer cells Induction a switch from PKM2 to (MCF-7) PKM1 Human prostate cancer cells ↑PKM1 protein level (PC-3) ↓PKM2 protein level ↓Aerobic glycolysis ↓hnRNPA1 and c-Myc-dependent hnRNPA1 ↓mTOR signaling ↑PK activity In vitro Human breast cancer cells ↓Glucose uptake (MDA-MB-231) ↓Lactate production ↓HK, LDHA and PKM2 proteins ↓PK activity In vitro and Human breast cancer cells ↑AMPK in vivo (MCF-7) ↓Protein synthesis Human prostate cancer cells ↓Lipogenesis, and aerobic glycolysis (PC-3) ↓mTORC1 Nude BALB/c mice ↓FAS protein level ↑p-ACC1 and p-HMGR In vitro and Human ovarian cancer cells ↓Lactate production and glucose in vivo (SKOV3 and 3AO) uptake Xenograft nude mouse ↓HK2, PKM2 mRNA and protein model level ↓GLUT1 mRNA level

Ginsenoside 20(S)‑ Rg3

Jo

Triterpenoid

Triterpenoid

87

[307]

[308]

[309]

Triterpenoid

In vitro

Human cervical cancer cells (HeLa)

-hederin

Triterpenoid

In vitro

Human oral cancer cells (SCC-25)

β-carotene

Tetraterpene

In vitro

Tetraterpene

In vitro

Human breast cancer cells (MCF-7) Human breast cancer cells (MCF-7)

Tetraterpene

In vitro

Human breast cancer cells (MCF-10a, MDA-MB-231 and MCF-7)

Tetraterpene

In vitro

Human prostate cancer cells (DU-145 and PC-3)

Tetraterpene

In vitro

Human prostate cancer cells (PC-3 and LNCaP)

Tetraterpene

In vitro

Human cervical cancer cells (HeLa) Human breast cancer cells

Lycopene

ro

-p

re

lP

ur na

Jo

Lycopene

of

Betulinic acid

↓PDK, LDH and PFK mRNA level ↓Activity of SCD-1 Incorporation of saturated fatty acids in cardiolipin ↓Proliferation ↑Apoptosis ↑Caspases-3 and caspase-9 activity ↓Bcl-2 ↑Bax ↓PI3K/Akt/mTOR signaling pathway ↓Cell growth ↓Cholesterol synthesis ↑Apoptosis ↑PPAR-γ mRNA ↓COX-2 ↑p21 gene expression ↑Cytochrome c release ↑ROS ↑Caspase-10, PIK3C3, IL1A, CYCS, ATM and Akt1 ↑MGST1 and ALDH1A3 ↓CYP2S1 ↓Proliferation ↑PPARγ-LXRα-ABCA1 pathway ↑ABCA1 ↑Cholesterol efflux G0/G1 cell cycle ↓Akt ↓Cyclin E and cyclin D1 ↓Cyclin-dependent kinase 4 ↑MDA level ↓GSH level ↑ROS

88

[310]

[311]

[312] [313]

[314]

[315]

[316]

[317]

-p

ro

of

(MCF-7) Human prostate cancer cells (PC-3) Human lung carcinoma cells (A549) Human liver cancer cells (HepG2) Human epidermoid carcinoma cells (A431)

Jo

ur na

lP

re

↑: Increase or up-regulation, ↓: decrease or down-regulation, : blockade, ACC1: acetyl-CoA carboxylase, Akt: protein kinase B, AKT-mTOR: protein kinase B-mammalian target of rapamycin, AMPK: AMP-activated protein kinase, ATM: ataxia-telangiectasia mutated, ATP: adenosine triphosphate, Bcl-2: B-cell lymphoma 2, Bcl-xL: B-cell lymphoma-extra-large, CDK: cyclin-dependent kinase, COX-2: cyclooxygenase-2, CYP2S1: cytochrome P450 2S1, DAPK2: DAP kinase 2, ERK1/2: extracellular signal-regulated protein kinase, FAK: focal adhesion kinase, FAS: fatty acid synthase, FLT-3: Fms like tyrosine kinase 3, GLUT1: glucose transporter 1, GSH: glutathione, HO-1: heme oxygenase-1, HIF-1α: hypoxia-inducible factor-1α, HK2: hexokinase-2, HMGCR: 3-hydroxy-3-methylglutaryl-coenzyme A reductase, HMGR: 3-hydroxy-3-methylglutaryl-coenzyme A reductase, hnRNPA1: heterogeneous nuclear ribonucleoprotein A1, Hsp70s:70 kilodalton heat shock proteins, IL-6: interleukin 6, LDH: lactate dehydrogenase, LDHA: lactate dehydrogenase A, MAPK: MAPKs: mitogen-activated protein kinase, MCT1: monocarboxylate transporter 1, MDA: malondialdehyde, MGST1: microsomal glutathione S-transferase 1, MMP: matrix metalloproteinase, mTOR: mammalian target of rapamycin, NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells, NRF2: nuclear factor erythroid 2-related factor 2, NSCLC: Non-small cell lung cancer, PDK: pyruvate dehydrogenase kinase, PFK: phosphofructokinase, PK: pyruvate kinase, PKM2: pyruvate kinase M2, PPAR-γ: peroxisome proliferator-activated receptor-γ, pSTAT3: phospho-STAT3, ROS: reactive oxygen species, SCD-1: steroyl-CoA-desaturase, SCO2: synthesis of cytochrome c oxidase 2, SREBP-1: sterol regulatory element-binding protein-1, STAT: signal transducer and activator of transcription, STIM1: stromal interaction molecule 1, TIGAR: TP53-induced glycolysis and apoptosis regulator, TIMP-1: tissue inhibitor of metalloproteinase, TNBC: triple-negative breast cancer cells, uPA: urokinase plasminogen activator, VCAM-1: vascular cell adhesion molecule, VDAC: voltage-dependent anion channel.

89

of

Table 3. The preclinical evidence of alkaloids and related therapeutic targets in regulating cancer metabolism. Types of study

Cell line(s)/cancer model(s)

Mechanism of action/metabolic effects

Berberine

In vitro

Colon cancer cells (HCT116 and KM12C)

In vitro and in vivo

Human glioma cells (P3, U251 and U87) Xenograft nude mouse model

In vitro and in vivo

Human gastric carcinoma cells (SGC7901 and AGS) Xenograft mouse model

ro

Compound

Jo

In vitro

Tomatidine

↓HIF-1α protein synthesis ↓mTOR pathway ↓Glucose metabolism ↓Glucose uptake ↓GLUT1, LDHA and HK2 ↓Glycolytic capacity ↑Apoptosis ↓AMPK/mTOR/ULK1 pathway ↓Tumor growth ↓AMPK/HNF4a Pathway G0/G1 phase cell cycle ↓Migration and invasion ↑AMPK and p-AMPK ↓MMP-3 ↓HNF4a ↓PKM2

[318]

↑p-ACC protein level ↓p-ACL protein level ↓LDH and PFK protein level ↑Citrate content ↑p-PKM2 protein level ATP energy depletion Unfolded protein response disruption ↓MMP-2 ↓c-fos protein expression ↓p-50

[322]

-p

re

lP

ur na

In vitro

Human colon cancer cells (HCT116) Human cervical cancer cells (HeLa) Human breast cancer cells (MCF-7)

In vitro

Human lung cancer cells (A549)

In vitro

Human fibrosarcoma cells (HT1080)

90

References

[319]

[320]

[321]

[323] [324]

of

↓NF-κB and AP-1 ↓ERK ↓Macropinocytosis ↓Intracellular glutamine level ↑Bax ↓Bcl-2 ↑UCP2 level through PGC-1α enrichment ↑SIRT1/PGC-1α/UCP2 axis ↓Ki-67 ↑Mitochondrial complexes (I and II) activity ↓ATP and NADH levels ↑Ratio of NAD+/NADH ↑SIRT1 activity ↑PGC-1α transcription activity ↓PI3K/Akt/mTOR pathway ↓p110a, Akt, mTOR and p70S6K ↓Cdk-2

In vitro and in vivo

Human pancreatic cancer cells (PANC-1 and MiaPaCa-2) Xenograft mouse model

Bouchardatine

In vitro and in vivo

Human colon cancer cells (HCT116, LOVO, SW-480 and SW-620) Xenograft mouse model

4-Chloro fascaplysin

In vitro and in vivo

Human prostate cancer cells (PC-3 and MIA-Pa-Ca-2) Human breast cancer cells (MDAMB-231) Human lung cancer cells (A549) Xenograft mouse model

Piperlongumine

In vitro and in vivo

[325]

[326]

lP

ur na

Jo In vivo

Neferine

re

-p

ro

Phellodendrine chloride

In vivo

Mouse colon adenocarcinoma cells (CT26) Human colon adenocarcinoma cells (DLD-1) Mouse model of colorectal tumor Human breast cancer cells (MCF-7, BT-549, MDA-MB-231 and MDAMB-453) Albino Wistar rat model of lung cancer

91

[327]

G2/M phase cell cycle ↑ROS ↓GSH ↓Thioredoxin reductase

[328]

PI3K/Akt/mTOR signaling axis

[329]

↓Glycoprotein ↑ATPases ↓PI3K/Akt/mTOR signaling ↓NF-κB, COX-2 and VEGF

[330]

of

In vitro and in vivo

Human liver cancer cells (Hep3B and Huh7) Zebrafish xenograft model

Dihydrosanguinarine

In vitro

Human pancreatic cancer cells (SW1990 and PANC-1)

Tetrandrine

In vitro and in vivo

Human colon cancer cells (SW620) Xenograft nude mice model

Nitidine chloride

In vitro

Human osteosarcoma cells (MG63 and U2OS)

Ellipticine

In vitro

Human endometrial adenocarcinoma cells (RL95-2)

re

lP

ur na

Jo In vitro

[331]

[331]

-p

ro

Aloperine

Piperine

↑Caspase-3, caspase-9 and Bax Bcl-2 ↓PI3K/Akt signaling pathway ↑Cleavages of PARP, caspase-3 and caspase-9 G2/M phase cell cycle Cdc2, cyclin B1 and cdc25C ↓Akt, and p-Akt (Ser473), p110α and p85 G2/M and G0/G1 phases cell cycle ↓mut-p53 protein ↓ERK phosphorylation ↓C-Raf level ↓mut-Ras ↑WT-Ras and WT-p53 ↓PI3K/Akt signaling pathway ↓BMP9 ↑BMP9 protein and mRNA ↓p-Akt 1/2/3 ↓p-PTEN ↓Proliferation ↑Apoptosis ↓Migration and invasion ↓SIN1 Expression G2/M phase cell cycle ↑Caspase activation ↑Cytochrome c and AIF ↑ ROS production ↑ERK ↑JNK ↑MAPKs ↓Proliferation ↑Apoptosis ↓HER2 ↓SREBP-1 and FAS expression

Human breast cancer cells (SKBR3, BT-474 and MCF-7)

92

[332]

[333]

[334]

[335]

of

Human pancreatic cancer cells (AsPC-1, Mia PaCa-2 and BxPC-3) Xenograft nude mouse model

re

NIn vitro and in methylhemeanthidine vivo chloride

Human liver cancer cells (HepG2)

ro

In vitro

[336]

[337]

-p

Capsaicin

↓EGF-induced MMP-9 expression ↓FAS mRNA level ↓FAS protein level G0/G1 phases cell cycle ↓de novo fatty acid synthesis ↓FAS activity and protein expression ↑ROS ↑Apoptosis G2-M phases cell cycle Akt signaling pathway ↓Glycolysis

Jo

ur na

lP

↑: Increase or up-regulation, ↓: decrease or down-regulation, : blockade, ACC1: acetyl-CoA carboxylase, ACL: ATP-citrate lyase, Akt: protein kinase B, AMPK: AMP-activated protein kinase, ATP: adenosine triphosphate, Bcl-2: B-cell lymphoma 2, BMP: bone morphogenetic protein, COX2: cyclooxygenase-2, EGF: epidermal growth factor, ERK1/2: extracellular signal-regulated protein kinase, FAS: fatty acid synthase, FASN: fatty acid synthase, GLUT1: glucose transporter 1, HER2: human epidermal growth factor receptor 2, HIF-1α: hypoxia-inducible factor-1α, HK2: hexokinase 2, JNK: c-jun NH2-terminal kinases, LDH: lactate dehydrogenase, LDHA: lactate dehydrogenase A, MMP: matrix metalloproteinase, mTOR: mammalian target of rapamycin, NADH: nicotinamide adenine dinucleotide, NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cell, PARP: poly(ADP ribose) polymerase, PFK: phosphofructokinase, PGC-1α: peroxisome proliferators activated receptor γ coactivator 1α, PI3K: phosphatidylinositol 3-kinases, PKM2: pyruvate kinase M2, PTEN: phosphatase and tensin homolog, ROS: reactive oxygen species, SIRT 1: Sirtuin 1, SREBP-1: sterol regulatory element-binding protein 1, UCP2: uncoupling protein 2, VEGF: vascular endothelial growth factor.

93

of

Table 4. The preclinical evidence of sulfur-containing compounds and related therapeutic targets in regulating cancer metabolism. Types of study

Cell line(s)/cancer model(s)

Sinigrin

In vitro and in vivo

Human liver cancer cells (HepG2) Sprague Dawley rat model of carcinogen-induced hepatotoxicity

Moringin

In vitro and in vivo

-p

re

ur na

In vitro

↓Proliferation ↑Apoptosis G0/G1 phases cell cycle ↑p53 ↑Bax ↓Bcl-2 Human neuroblastoma cells (SH↑Bax, p53 and p21 SY5Y) ↑Gene expression of both caspase-3 and caspase-9 ↓Nuclear translocation of NF-κB Human liver cancer cells (Hep3B) ↓Proliferation ↑Extrinsic and intrinsic apoptosis ↑ROS ↑Caspases-9, caspase-8, caspase-2 and caspase-3 Human cervical cancer cells (HeLa) ↓IL-3-induced STAT5 signaling ↓STAT5 and NF-κB Human brain astrocytoma cells (CCF- ↑Apoptosis STTG1) ↓Bcl-2 ↑Bax ↑p53 ↓5S rRNA ↑Nrf2 Human prostate cancer cells (PC-3) ↓Proliferation ↑Apoptosis Human breast cancer cells (MDA↓TAP-induced MMP-9 MB-231) NF-κB and AP-1 Human colon cancer cells (SW480) ↓p-FAK, p-Akt, and p-ERK1/2 Human cervical cancer cells (Caski) ↓FAK/ERK signaling pathway Human lung cancer cells (A549) ↓FAK/Akt signaling pathway Human glioblastoma cells (T98G)

lP

In vitro

Mechanism of action/metabolic effects

In vitro

Jo

Glucomoringin- In vitro Isothiocyanate Isothiocyanates In vitro and in vivo

ro

Compound

94

References [208]

[209]

[210]

[211] [212]

[213] [214]

In vitro

Human prostate cancer cells (PC-3)

of

3-Butenyl isothiocyanate

↓COX-2 and mPGES-1 ↓VEGF, HIF-1, CXCR4, MMP-9 and MMP-2 ↓Expression of microsomal prostaglandin E synthase-1 ↑ROS ↑Caspase-3 ↓LDH

ro

In vitro

re

-p

Sulforaphane

Human prostate cancer cells (DU145) Human osteosarcoma cells (U2OS) Xenograft nude mouse model Human colon cancer cells (HT-29)

[215]

[216]

Jo

ur na

lP

↑: Increase or up-regulation, ↓: decrease or down-regulation, : blockade, Akt: protein kinase B, AP-1: activator protein 1, COX-2: cyclooxygenase 2, CXCR4: C-X-C chemokine receptor type 4, ERK1/2: extracellular signal-regulated protein kinase, FAK: focal adhesion kinase, HIF-1: hypoxiainducible factor-1, IL-3: interleukin 3, LDH: lactate dehydrogenase, MMP: matrix metalloproteinase, mPGES-1: Microsomal prostaglandin E synthase-1, NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cell, Nrf2: Nuclear factor erythroid 2-related factor, ROS: reactive oxygen species, STAT: signal transducer and activator of transcription, TPA: 12-O-tetradecanoylphorbol-13-acetate, VEGF: vascular endothelial growth factor.

95

of

Table 5. The preclinical evidence of miscellaneous phytochemicals and related therapeutic targets in regulating cancer metabolism. Types of study

Cell line(s)/cancer model(s)

3,3′Diindolylmethane

In vitro

Human liver cancer cells (HepG2 and SMMC-7721) Human colorectal adenocarcinoma cells (HCT-116, LoVo, SW480, Caco-2 and HT-29) Human ovarian cancer cells (SKOV3 and A2780) Xenograft nude mouse model Human colon cancer cells (HT29 and HCT116) (Min/+) mouse colon tumor model Human breast cancer cells (MCF-7 and SK-BR-3) Human breast cancer cells (MDA-MB231) Murine breast tumor cells (4T1)

In vitro and in vivo In vitro

Female (NOD/SCID) mouse model of lung metastasis

In vitro

In vitro and in vivo

Human prostate cancer cells (PC-3 and DU-145)

Human lung adenocarcinoma cells (NCI-H1437, Calu-6, A549 and NCIH460) Xenograft mouse model 96

References

↑Apoptosis ↑p-p38 MAPK ↑Endoplasmic reticulum stress response ↓Cyclin D1

[340]

↓p-STAT3 and p-Akt ↓STAT3 and Akt signaling pathways ↓Bcl-2, MMPs, Mcl-1, VEGF and HIF-1α ↓ERK1/2 and COX1/2

[342]

↓GPER and ERα ↓p-ERK and EGFR Reversal of EMT ↓N-cadherin ↓β-catenin signaling ↓β-catenin expression ↑β-catenin phosphorylation ↑GSK-3β ↑E-cadherin G2 phase cell cycle ↑ROS/ERK1/2 pathway ↓MMP-2 and MMP-9 ↓p-Akt and p-mTOR ↑Apoptosis ↓Akt ↑FOXO3a/EGR1/SIRT1 signaling ↑Bim

[344]

-p

ur na

In vitro and in vivo

Jo

Shikonin

re

In vitro and in vivo

lP

In vitro

Mechanism of action/metabolic effects

ro

Compound

[341]

[343]

[345]

[346]

[347]

In vitro

Indole-3-carbinol

In vivo

Bixin

In vitro

Rapanone

In vitro and in vivo

Jo

of

ur na

Methyl protodioscin

ro

Pinitol

In vitro and in silico In vitro and in vivo In vitro

-p

In vitro

re

Amygdalin

Human colon cancer cells (HCT116 and ↓HIF-1α SW620) ↓mTOR/p70S6K1/4E-BP1/eIF4E signaling Xenograft mouse model pathway ↑Akt Human prostate cancer cells (PC3, ↓Cdk 1, cdk 2 and cdk 4 LNCaP and DU-145) ↓cyclin A, cyclin B and cyclin D3 ↓Akt/mTOR pathway ↓p-Akt, p-Raptor and p-Rictor Human breast cancer cells (SK-BR-3) ↑Bax ↓Bcl-2 Human cervical cancer cells (HeLa) ↑Bax Xenograft mouse model ↓Bcl-2 Human chronic myelogenous leukemia ↑Apoptosis cells (KBM-5) ↓NF-κB activation Human lung cancer cells (H1299) ↓TNF-induced IKK activation Human myeloma cells (U266) ↓Cyclin D1, COX-2 and c-Myc Human cervical cancer cells (Hela) G2/M phase cell cycle ↑ROS ↓Caspase-8 and caspase-9 Xenograft mouse model ↑Caspase-dependent apoptotic pathway ↓NF-κβ ↓VEGF-A and MMP-9 Human melanoma cells (A2058) ↑Apoptosis G2/M phase cell cycle Human liver cancer cells (HepG2) ↓TP generation Male Wistar rats ↑ROS generation ↑Ca2+ and cytochrome c release ↓ΔΨ and ATP Human breast cancer cells (MDA-MB- ↑ROS generation 231) ↑Cleavages of PARP Nuclear localization of AIF Human breast cancer cells (MCF-7 and ↓NF-κB activation MDA-MB-231) ↓CXCR4

lP

In vitro and in vivo

Oxyresveratrol

In vitro and in silico

Butein

In vitro

97

[348]

[350]

[351] [352] [353]

[354]

[355]

[356] [357]

[358]

[359]

of

ro

Human pancreatic cancer cells (PANC28, MIA PaCa-2 and AsPC-1) Human liver cancer cells (HepG2) Human prostate cancer cells (DU-145) Human myeloma cells (U266)

Jo

ur na

lP

re

-p

↑: Increase or up-regulation, ↓: decrease or down-regulation, : blockade, Akt: protein kinase B, Bcl-2: B-cell lymphoma 2, CDK: cyclin-dependent kinase, COX-1,2: cyclooxygenase-1 and -2 , CXCR4: CXC chemokine receptor-4, EGFR: epidermal growth factor receptor, EMT: epithelial-tomesenchymal transition, ERK: extracellular signal-regulated kinases, ERα: estrogen receptorα, GPER: G protein-coupled estrogen receptor, GSK-3β: glycogen synthase kinase 3β, HIF-1α: hypoxia-inducible factor-1α, MAPK: mitogen-activated protein kinase, MMP: matrix metalloproteinase, mTOR: mammalian target of rapamycin, NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cell, p-ERK: phosphorylated ERK, ROS: reactive oxygen species, STAT: signal transducer and activator of transcription, TNBC: triple-negative breast cancer, TNF-α: tumor necrosis factorα, VCAM-1: vascular cell adhesion molecule, VEGF: vascular endothelial growth factor.

98