Repurposing of plant alkaloids for cancer therapy: Pharmacology and toxicology

Journal Pre-proof Repurposing of plant alkaloids for cancer therapy: Pharmacology and toxicology Thomas Efferth, Franz Oesch

PII:

S1044-579X(19)30408-0

DOI:

https://doi.org/10.1016/j.semcancer.2019.12.010

Reference:

YSCBI 1734

To appear in:

Seminars in Cancer Biology

Received Date:

24 July 2019

Accepted Date:

15 December 2019

Please cite this article as: Efferth T, Oesch F, Repurposing of plant alkaloids for cancer therapy: Pharmacology and toxicology, Seminars in Cancer Biology (2019), doi: https://doi.org/10.1016/j.semcancer.2019.12.010

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Repurposing of plant alkaloids for cancer therapy: Pharmacology and toxicology

Thomas Efferth1* and Franz Oesch2

Department of Pharmaceutical Biology, Johannes Gutenberg University, Mainz, Germany

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Institute of Toxicology, Medical Center, Johannes Gutenberg University, Mainz, Germany

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* Corresponding author: Staudinger Weg 5, 55128 Mainz, Germany. Tel: 49-6131-3925751; Fax: 49-

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Running title: Alkaloids for cancer therapy

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611-3923752; E-mail: [email protected]

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Abstract Drug repurposing (or repositioning) is an emerging concept to use old drugs for new treatment indications. Phytochemicals isolated from medicinal plants have been largely neglected in this context, although their pharmacological activities have been well investigated in the past, and they may have considerable potentials for repositioning. A grand number of plant alkaloids inhibit syngeneic or xenograft tumor growth in vivo. Molecular modes of action in cancer cells include induction of cell cycle arrest, intrinsic and extrinsic apoptosis, autophagy, inhibition of angiogenesis and glycolysis, stress and anti-inflammatory responses, regulation of immune functions, cellular differentiation, and inhibition of invasion and metastasis. Numerous underlying signaling processes are affected by plant alkaloids. Furthermore, plant alkaloids suppress carcinogenesis, indicating chemopreventive

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properties. Some plant alkaloids reveal toxicities such as hepato-, nephro- or genotoxicity, which disqualifies them for repositioning purposes. Others even protect from hepatotoxicity or cardiotoxicity of xenobiotics and established anticancer drugs. The present survey of the published literature clearly demonstrates that plant alkaloids have the potential for repositioning in cancer therapy. Exploitation

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of the chemical diversity of natural alkaloids may enrich the candidate pool of compounds for cancer chemotherapy and –prevention. Their further preclinical and clinical development should follow the

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same stringent rules as for any other synthetic drug as well. Prospective randomized, placebocontrolled clinical phase I and II trials should be initiated to unravel the full potential of plant alkaloids

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for drug repositioning.

Introduction

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Key words: Natural products, Phytochemicals, Network pharmacology, Targeted chemotherapy

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The term drug repurposing (or repositioning, re-profiling) describes the use of already approved drugs against one disease for re-use against another disease [1]. Proof-of-principle examples are the new

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applications of thalidomide against multiple myeloma and leprosy as well as sildenafil against erectile dysfunction and pulmonary hypertension. As a matter of fact, the number of newly released FDAapproved drugs decreased since the 1990s, and there is an urgent need for novel drugs against cancer as well as other diseases [2]. Old drugs have several advantages compared to the development of new entities: Their safety and toxicity profile as well as their pharmacokinetic behavior are already wellstudied in human beings, which considerably decreases the drug developmental costs [3]. Issues of intellectual property with old drugs may be overcome by developing novel derivatives based on the chemical scaffolds of old drugs [4]. New anticancer drugs are required because of the development of 2

tumor resistance to established drugs and their severe, partwise life-threatening side effects [5]. Drug resistance may occur due to the occurrence of mutations in critical genes and heterogeneic tumor subpopulations, which are non-responsive to treatment [6-9]. The quest for drug repositioning opportunities is greatly facilitated by computational approaches, which allow the identification of novel targets and signaling pathways for old drugs [10-14]. A timely overview of synthetic drugs considered for repositioning is given by Olgen and Kotra (2018) [15]. In the present review, we focus on natural compounds, i.e. alkaloids from plants. During the past years, the main spotlight of drug repositioning research was on FDA-approved synthetic drugs and on the market for other disease indications. The field is, however, much larger and the entire area of medicinal herbs and their isolated phytochemicals have been largely neglected as of

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yet. However, phytochemicals offer a huge potential for being repositioned. During the past decades, several ten-thousand phytochemicals have been isolated from plants used in traditional medical system all over the world. These medicinal plants have been applied for hundreds or thousands of years for diverse disease conditions. In addition to traditional medicine, rationale phytotherapy and

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pharmacognosy as disciplines of academic pharmacy programs led to the development of numerous approved phytotherapeutics on the market.

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We give here just a few examples out of many others to illustrate the suitability of isolated phytochemicals for drug repositioning, since they reveal more than one specific pharmacological activity:

Artemisinin from Artemisia annua, reveals not only anti-malarial activity, but is also active

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against cancer, certain viral infections, trypanosomiasis, schistosomiasis etc. [16, 17]. 

Colchicin from Colchicum autumnale kills cancer cells in vitro, but cannot be used in cancer

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patients because it is too toxic. Instead, it is clinically applied to treat gout. Ergot alkaloids from Claviceps purpurea are (partial) dopamine receptor and serotonin

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receptor agonists, α-adrenoreceptor antagonist, inhibit prolactin and somatotropin release, act against migraine, and contract uterus musculature and blood vessels. The synthetic ergot derivative, bromocriptine is also active against Parkinson disease. Quinine, quinidine, and cinchonine from Cinchona officinalis are active against malaria and

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cardiovascular diseases.

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Tetrahydrocannabiol and cannabidiol from Cannabis sativa are banned for its addictive potential. However, they were recently reconsidered for pain treatment in patients suffering from late stage cancer or multiple sclerosis.

To our opinion, it is worth investigating, whether phytochemicals exert therapeutic potentials to treat cancer. The idea is not to promote unproven herbal preparations from complementary and alternative medicine, but to scientifically investigate chemically defined compounds from medicinal 3

plants and to take them as chemical lead scaffolds for chemical derivatization. Novel derivatives are then supplied to the pharmaceutical drug development pipeline in a comparable manner as synthetic drugs as well. The validity of this concept is substantiated by surveys of the National Cancer Institute, USA, showing that 75 % of all anticancer drugs are in the one way or another based on natural resources [18, 19]. This astonishingly high percentage emphasizes the relevance of naturally derived drugs for cancer chemotherapy. It can be envisioned that nature developed complex biosynthesis routes to produce phytochemicals during evolution of plants on earth as chemical defense against microbial attack (viruses, bacteria, protozoans) and herbivores (insects, worms, mammals). With the help of medical chemistry, these phytochemicals can serve as lead compounds to adapt and optimize them to take

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advantage of their pharmacological activities and to treat diseases in patients.

There is a plethora of literature on the cytotoxic activity of natural compounds from diverse chemical classes, e.g. terpenoids, lignans, steroids, flavonoids, naphthoquinones, anthranoids, plant acids, saponins, alkaloids etc. It is beyond the scope of this review to report on all data available.

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Rather, we focused on one chemical class of phytochemicals, which is long known for its pharmacological activities, i.e. alkaloids.

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We performed a systematic review by screening the PubMed database with the search terms “repositioning/repurposing + alkaloid + plant + cancer + in vivo/xenograft”. Papers written in English were included until June 20, 2019. Since there are more than 3000 papers on the cytotoxic activity of

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plant alkaloids towards cancer cells in general and since many compounds cytotoxic in vitro do not reveal tumor inhibition in living organisms, we restricted our search to investigations showing anticancer activity of plant alkaloids in vivo. Our search strategy was confined to alkaloids that are

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already known for their pharmacological activity for other diseases than cancer, in order to emphasize their potential for drug repurposing. We also highlighted the toxicity of these plant alkaloids. This

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represents an important aspect, if it comes to clinical drug development. Only those compounds can be further considered which reveal convincing safety and tolerability. To further focus our review, we did not include publications on combination treatments of plant alkaloids with other drugs.

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Furthermore, (semi)synthetic derivatives of plant alkaloids and nanotechnological preparations including plant alkaloids were also excluded. The intention of the present review was to consider, whether plant-derived alkaloids with diverse

pharmacological activities may also be further developed for cancer chemotherapy. As a result, we came up with a panel of alkaloids, which are compiled in Table 1. This table shows not only the pharmacological activities beyond cancer, but also the plants they have been isolated from. Most of these plants have been used in traditional medicine in Asia, Near East or South-America since ages. Their medical uses have also been presented. By literature mining, we further analyzed, whether these 4

plant-derived alkaloids might be appealing candidates for drug repositioning in cancer therapy. Based on the available safety and efficacy data in vivo, plant-derived alkaloids may be discussed as lead compounds for further drug development.

Inhibition of primary tumors Induction of cell cycle arrest In this review, we considered reports performed both with syngeneic murine or rat tumors transplanted to rodents as well as human xenograft tumors transplanted to nude mice. Syngeneic tumors have the advantage that the host animals have an intact immune system, which means that

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immune defense mechanisms against tumors contribute to the overall anticancer activity of investigated compounds. Although xenograft tumors are transplanted to immuno-deficient mice, this model has the advantage that human tumors can be investigated in living organisms (albeit not in human patients).

An early reaction of tumor cells to toxic insults is the induction of cell cycle arrest, which allows

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cells either to repair damaged sites or to induce programmed cell death. Cell cycle arrest can occur at different phases of the cell cycle. This has been shown not only for synthetic drugs, but also for

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phytochemicals [20-24]. Defined checkpoints serve the cellular control of genomic integrity. Arrest at these checkpoints enable the repair of lesions. The G0/1 and G2/M checkpoints allow the repair of

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DNA lesions, while the S-phase arrest enables repair during DNA replication. The cell cycle is driven and by three regulatory levels: (1) cyclins drive the cell cycle from G1 to S, G2 and M phases; (2) cyclin dependent kinases (CDKs) control the activity of cyclins; (3) CDK inhibitors control CDKs (p21, B). ATM

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and ATR are sensor proteins which regulate the tumor suppressor p52 to control cyclins and CDKs in various cell cycle phases to induce DNA repair. Plant alkaloids induced either G0/G1 arrest or G2/M arrest. In few cases even S phase arrest was reported (Table 2). Under conditions, where DNA repair

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cannot be performed (e.g. growth factor deficiency, overload of the DNA repair capacity etc.), p53 can

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act as sensor to induce apoptosis.

Induction of apoptosis Numerous investigations on phytochemicals describe the inhibition of tumor growth by induction of classical programmed cell death (apoptosis) in vitro [25-30]. There are much less in vivo investigations. Table 3 shows a large panel of phytochemicals from diverse alkaloid classes, which induced apoptosis in both syngeneic and xenograft tumors. A broad spectrum of different tumor entities rather than certain tumor types were inhibited, e.g. colorectal, breast, gastric, endometrial, cervical, hepatocellular, lung, and prostatic carcinoma, glioblastoma, melanoma, osteosarcoma, as well as rare tumors such as pheochromocytoma, neuroblastoma, and cholangiocarcinoma. The alkaloids analyzed 5

seem to exert a general anticancer activity. It is pleasing that also some rare tumor types have been investigated. Frequently, the treatment options available for rare tumors are not satisfactory. Therefore, the treatment of pheochromocytoma, neuroblastoma, and cholangiocarcinoma with plantderived alkaloids may offer an opportunity to improve the outcome of these diseases. The majority of investigations reported the induction of the intrinsic, mitochondrial pathway of apoptosis by plant alkaloids. Mitochondria are central for the intrinsic pathway of apoptosis. Members of the Bcl-2 family are located in the outer mitochondrial membrane. There are pro-apoptotic members (Bax, Bak etc.) and anti-apoptotic members (Bcl-2, Bcl-xL etc.), which form homo- and heterodimers. Upon suitable stimuli (oxidative stress, xenobiotics, cytotoxic drugs etc.), the formation of pro-apoptotic dimers prevail, leading to a release of cytochrome C from the inside of mitochondria

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to the cytosol. Then, cytochrome C binds to Apap-1, which in turn binds to procapsapse-9. This complex has been termed apoptosome. Procaspase-9 is cleaved by the apoptosome into caspase-9 (initiator caspase). This protease cleaves procaspase-3 into the active caspase-3 (effector caspase), which executes cell death. In parallel to cytochrome c, SMACs are released from the mitochondria into the

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cytosol, which bind and inhibit IAPS. IAPs (cIAP-1/2, XIAP) are proteins that inhibit caspases. IAP inhibition by SMACs allows activation of caspases by autophagosomes [31]. As shown in Table 3, the

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induction of the intrinsic mitochondrial pathway is well documented for several plant alkaloids with anticancer activity.

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Only a few authors described the involvement of Fas as major player of the extrinsic apoptotic pathway by plant alkaloids. The Fas ligand (or other ligands such as TNF-α) bind to the Fas receptor or other death receptors of the TNF-α receptor family. Binding of ligands to their corresponding receptors

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lead to the formation FADD or TRADD complexes, which activates caspase-8 (initator caspase). cIAP1/2 and FLIP are negative regulators that can inhibit the extrinsic receptor-driven pathway of apoptosis [31]. Based on the available data (Table 3), it is not clear, whether or not intrinsic apoptosis is more

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important for plant alkaloids than the extrinsic mode of cell death for the anticancer activity of some plant alkaloids. It is possible that the extrinsic death receptor-driven pathway has been less

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investigated, but is of similar importance as intrinsic apoptosis. This open question should be addressed in more detail in the future. It is a striking feature that the alkaloids induced apoptosis was independent of their chemical

structure or biological function. This indicates that apoptosis may not be the primary target of these compounds, but that the actual drug targets are more upstream from the apoptosis cascade. Most – if not all - clinically established anticancer drugs address different target structures (e.g. microtubule, DNA topoisomerases I or II, DNA biosynthetic enzymes, DNA lesions, hormones, growth factor receptors, signaling kinases etc.). However, the interaction of these anticancer drugs with their targets 6

finally leads to the induction of apoptosis further downstream in the signaling cascade. The same may be true for the diverse plant alkaloids shown in Table 3.

Induction of non-apoptotic cell death Unraveling the molecular mechanisms of apoptosis during the past three decades also brought up results showing that programmed cell death can be committed in a non-apoptotic fashion. One of the most prominent caspase-independent, non-apoptotic mechanisms is autophagic cell death. Human homologues of the atg genes from Saccharomyces cerevisiae play a major role in autophagy. mTOR and AMPK phosphorylate the Atg1 homologues ULK-1 and ULK-2. Their dephosphorylation results in activation of these two kinases, which then phosphorylate and activate the Atg6 homologue Beclin-1.

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ULK-1/2 and Beclin-1 are parts of a larger protein complex, which also consists of VPS34. This protein activates further downstream events involving further Atg homologues leading to the formation of the autophagosome and activation of the LC3 protein, which enables fusion with lysosomes. Then, these vesicles release their hydrolytic enzymes that degrade cellular proteins leading to autophagic cell

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death [32, 33].

Autophagy in tumors by phytochemicals in general and specifically by plant alkaloids has been

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less intensively investigated than apoptosis [34-36]. Nevertheless, quite a number of reports deliver convincing evidence that autophagy represents an important mechanism involved in the inhibition of

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tumor growth in vivo (Table 4). Autophagy can occur either alone or together with apoptosis upon treatment with some plant alkaloids.

In recent years, further modes of cell death have been described. Although this novel field of

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research has not been well studied yet in the context of plant alkaloids, a few authors reported novel non-apoptotic cell death modes such as pyroptosis (inflammatory cell death) or oncosis (ischemic cell death) [37, 38]. The role of non-apoptotic forms of cell death and their contribution to the overall

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inhibition of tumor growth by plant alkaloids in comparison to apoptosis and autophagy deserves

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further attention in the years to come.

Inhibition of tumor angiogenesis While early in tumor development small tumors maintain their supply of nutrients and oxygen by passive diffusion from the surrounding normal tissue environment, larger tumors cannot. They suffer from hypoxic areas. Tumor cells react to this challenge by a process called angiogenic switch. The transcription factor HIF-1α activates expression of proteins that stimulate the formation of new blood vessels (neoangiogenesis) growing into the tumor. One of the best known angiogenic factors is VEGF.

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There is a balance of proteins that act in a pro-angiogenic (VEGF, bFGF, TGF-β1, IGF, G-CSF and others) or anti-angiogenic fashion (e.g. ANG, END, INFα, p53) [39, 40]. The formation of novel vessels represents a typical feature of progressive tumors. The inhibition of neoangiogenesis became an important treatment principle in the past years and several angiogenesis inhibitors were market as anticancer drugs (e.g. bevacizumab) [41, 42]. The inhibition of angiogenesis is also an important mechanisms of natural products and their derivatives [43-45]. As can be seen in Table 5, a broad range of tumor models have been used to investigate the antiangiogenic effects of plant alkaloids in vivo, including the downregulation of VEGF and its receptors, as well as signaling molecules such as AKT, SRC, FAK, ERK, p53, and transcription factors

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such as NFκB and mTOR. Other typical regulators of angiogenesis have not been reported for syngeneic or xenograft tumors yet. Future investigations should, therefore, focus on other angiogenesis regulators than VEGF to explore the full mechanistic regulation of angiogenesis inhibition by plant

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alkaloids.

Inhibition of signal transduction

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Cellular mechanisms such as cell death, angiogenesis, differentiation, stress response, immune response, anti-inflammatory response etc. are all driven and regulated by signal transduction

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pathways. Therefore, it is important to understand the signaling routes that are affected upon treatment of tumors with phytochemicals [46-50]. As can be seen from Table 6, plant alkaloids influenced cellular signaling by many different pathways. It is a general feature of most natural product

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that they are not mono-specific, but act in multi-specific modes of action. Therefore it comes as no surprise that multiple signaling pathways are either activated or shut off by alkaloids. Numerous transcription factors were described to be affected by plant alkaloids, including

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NFκB, MYC, FOS, CREB, WT1, mTOR and others. The WNT/β-catenin, ERK-, JNK-, and AKT-related pathways, as well as STAT and AMPK-related pathways all have been reported to be involved in plant

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alkaloid-induced cellular effects.

Other mechanisms In addition to angiogenesis, several other mechanisms play a role for the antitumor activity of plant alkaloids, albeit these mechanisms have been much less investigated as yet. In comparison to the above mentioned mechanisms, few papers report on the regulation of immune function (release of cytokines, upregulation of innate immune responses), the anti-inflammatory activity, stress response (antioxidant stress response genes, endoplasmic reticulum stress, heat shock protein HSP70), and alterations in tumor metabolism (impaired aerobic respiration and glycolysis), and tumor 8

differentiation upon treatment with plant alkaloids (Table 7). These modes of actions of plant alkaloids warrant more detailed investigation in the future to better understand their role for tumor inhibition.

Inhibition of invasion and metastasis The chapters above all deal with primary tumors. Most patients die, however, not because of their primary tumors, but because the primary tumors invade the neighboring tissues and form lymph node metastases or metastases in distant organs after spreading of tumor cells via the blood system. The metastatic process of progressive tumors with its different steps (local invasion, intravasation, circulation, extravasation and proliferation) represents, therefore, a mechanism of utmost importance for the survival prognosis of cancer patients.

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Loss of contact inhibition and altered cell adhesion are important for invasion and migration of tumor cells. Migrating cells decrease the expression of E-cadherin (which regulates adhesion between epithelial cells) and upregulate the expression of N-cadherin (which mediates the interaction between tumor and stroma cells). Tumor cells degrade the extracellular matrix (ECM), which maintains tissue

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structures and acts as barrier for cell invasion. Among the ECM constituents are collagens, fibronectin, laminins proteoglycans and many others. Cellular receptors of ECM constituents are integrins.

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Proteolytic enzymes of ECM are uPA and MMPs. Inhibitors of MMPs are TIMPs [51, 52]. The capability of tumor cells to migrate is increased by a phenotypic change of epithelial to mesenchymal cellular

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features (e.g. downregulation of cytokeratin as epithelial marker and upregulation of vimentin as mesenchymal marker) to facilitate the metastasis process. Once the metastasizing cells reached their target organ, they differentiate back to epithelial cells. This phenomenon has been termed epithelial-

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mesenchymal transition (EMT) [53, 54]. Chemokines (e.g. CXCRs) navigate metastasizing tumor cells into certain organs and favor their nidation there – a phenomenon termed homing factor. Typical organs of metastasis are lung, liver, and brain bone marrow. Certain transcription factors, e.g. SNAIL-

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1/2 and SLUG, orchestrate the expression of these invasion and metastasis factors. Numerous investigations pointed to the inhibition of metastatic tumors by phytochemicals [55-

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59]. We report here on papers, which describe either the inhibition of metastases by plant alkaloids in vivo or the inhibition of primary tumors in vivo and mechanisms of metastasis inhibition in vitro (Table 8). Plant alkaloids inhibited metastasis process into the lung and liver, inhibited EMT (upregulation of mesenchymal markers such as vimentin, downregulation of epithelial markers such as cytokeratin), inhibited matrix metalloproteinases (MMP-2, MMP-3, MMP-9, MMP-13), the metastasis-regulating transcription factors SNAIL-1 and SNAIL-2, uPA, cathepsin C etc. Among the adhesion molecules, the upregulation of E-cadherin and downregulation of N-cadherin was described. Several signal transduction pathways were not only inhibited in primary tumors (see chapters above), but also in metastasis by plant alkaloids, e.g. WNT/β-catenin, JAK, STAT, ERK, AMPK, and TGF-β 9

signaling etc. Mechanisms of plant alkaloid actions found in primary tumors (see Tables 2-5) were also observed in metastasis, e.g. cell cycle arrest, apoptosis, and angiogenesis inhibition. Interestingly, inflammatory markers (e.g. COX-2, PGE2) were also inhibited in metastasis by alkaloids, indicating that inflammation may not only play a role for initial tumorigenesis, but also for the metastatic process. The activation of natural killer cell activity by theophylline is a clue that plant alkaloids affect the immune system to exert anti-metastatic effects. This aspects requires more attention, and more investigations are required with more plant-derived alkaloids and more tumor types. Especially, the influence of the immune system should be compared in tumor-bearing immunocompetent and immuno-deficient mice.

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Chemoprevention of carcinogenesis

All results presented so far in this review article focused on the tumor treatment, i.e. eradication of already established tumors. Another aspect that has to be taken into account is the prevention of tumor development from the beginning on. Chemoprevention is an important field in cancer research,

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as long as all established therapy options such as chemotherapy, radiotherapy, immunotherapy and surgery do not reveal satisfying success rates to reliably cure cancer [60, 61]. As natural products are

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frequently considered as being well tolerated with few side effects, chemoprevention of carcinogenesis by phytochemicals may represent an attractive strategy to combat cancer [62-64].

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Plant alkaloids product may prevent carcinogenesis by chemicals (chemical carcinogenesis), irradiation (physical carcinogenesis) and viral infections (biological carcinogenesis). A number of reports found that the incidence of tumors induced by chemical carcinogens (BP, NKK, DEN, DMBA,

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DMH, DSS, urethane) were significantly reduced by co-application of plant alkaloids (Table 9). Several papers describe the chemopreventive effects of plant alkaloids on UV-B light induced skin carcinogenesis as example of physical carcinogenesis (Table 9).

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Plant alkaloids have not been investigated yet in the context of biological carcinogenesis, i.e. virally induced tumors. However, the expression of the lymphoma-inducing Epstein-Barr protein EBNA-1 was

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downregulated in nasopharyngeal xenograft tumors by berberine [65]. This indicates that plant alkaloids may bear the potential also to prevent virus-induced carcinogenesis. Another approach to investigate the chemopreventive activity of plant alkaloids was the

application of genetically manipulated animals, which spontaneously develop tumors, e.g. ApcMin/+ mice or TRAMP mice. Alternatively, non-manipulated tumor cells were transplanted in low number into animals. In all these cases, some plant alkaloids efficiently inhibited carcinogenesis (Table 9).

Toxicity of plant alkaloids 10

The use of plant alkaloids for cancer therapy depends not only on their efficacy to inhibit tumor growth, but also on their tolerability by normal tissues. Although natural products in general are frequently considered as being safe and although many natural products are indeed safe, others are not [66-72]. Therefore, the testing for toxicities exerted by plant alkaloids represents a sine qua non condition in the drug development process in the same manner, as it is performed for synthetic drugs. As shown in Table 10, organ toxicities have been observed in animals transplanted with syngeneic tumors and treated with piperine, piplartine, or oxymatrine, such as hepatotoxicity and nephrotoxicity. While these acute toxicities might be reversible after cessation of drug treatment, it is alarming that some alkaloids seem to stimulate tumor growth and metastasis or act as co-carcinogens (capsaicin, piperine). Others seem to be genotoxic (sanguinarine, harmine, caffeine). As a matter of

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course, drugs applied to cure cancer have to be neither genotoxic nor carcinogenic. In addition to DNAdamaging agents which initiate tumorigenesis, caffeine has been found to stimulate mammary gland development. This result might be interpreted as a proliferation-promoting effect, which is also not desirable for antitumor drugs. These plant alkaloids are, hence, not suited as candidates for drug

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repurposing in cancer therapy.

Other alkaloids reveal milder side effects such as inflammation (theophylline) or no observed

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side effects (noscapine, sinomenine, coptisine, matrine). These alkaloids might be more suitable for further repositioning in cancer therapy than the above mentioned toxic alkaloids. Interestingly, there are also authors reporting on plant alkaloids that prevented laboratory

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animals from toxicity caused by other agents. Berberine protected from the gastrointestinal mucosa from heavy alcohol consumption and doxorubicin-induced cardiomyopathy. Nuciferine protected from nicotine-induced liver injury (Table 10). These two alkaloids may, therefore, be beneficial partners for

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combination chemotherapy together with other established anticancer drugs. This aspect deserves

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further attention in the future.

Conclusion and perspectives

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There is a grand number of alkaloids derived from plants that could be considered for repositioning in cancer therapy, because they inhibited the growth of syngeneic and xenograft tumors in vivo. A lot is known about the molecular modes of action in cancer cells, e.g. induction of cell cycle arrest in G0/G1 cell cycle phases, induction of intrinsic and extrinsic apoptosis, autophagy and other modes of nonapoptotic cell death, inhibition of angiogenesis and glycolysis, stress and anti-inflammatory responses, regulation of immune functions, induction of cellular differentiation, inhibition of invasion and metastasis. All these mechanisms are regulated by specific signal transduction processes, which were affected by plant alkaloids. Furthermore, plant alkaloids suppressed carcinogenesis, indicating that they might be used as chemopreventive drugs. As all pharmacologically active drugs, some plant 11

alkaloids already at therapeutically potentially useful doses revealed toxicities such as hepato- nephroor genotoxicity, which disqualifies them for repositioning purposes. Others were described to even protect from hepatotoxicity or cardiotoxicity of xenobiotics and established anticancer drugs. The present survey of the published literature demonstrates that plant alkaloids may have the potential to be repositioned for cancer therapy. Exploitation of the chemical diversity of natural alkaloids may enrich the candidate pool of compounds for cancer chemotherapy and –prevention. Previously, natural products have sometimes been critically discussed and called dirty drugs, because they are not mono-specific, but exert multiple effects. This multi-specificity however, turned out as selection advantage during evolution of plant life, because multi-specific compounds are less

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prone to resistance development than mono-specific ones [73]. During the past decades, it turned out that many synthetic drugs are also not mono-specific. This is actually the basis of the entire concept of drug repositioning and increasingly emerges as considerable advantage in the development of new strategies to combat diseases such as cancer.

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This review does not only show the achievements of the past years to understand the anticancer activity of plant alkaloids, it also discloses gaps and deficiencies in research. For example, less is still known on the role of stem cells or the microenvironment for the activity of plant alkaloids.

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The mechanisms behind the influence of alkaloids on immune system, on anti-inflammatory and stress response reactions, on cancer metabolism and on tumor differentiation are not well understood.

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Epigenetics as new field of research in many disciplines of life sciences has been barely investigated in the context of alkaloids. How do plant alkaloids influence DNA methylation, histone acetylation or miRNA regulation? These and other questions deserve to be addressed in the future to better evaluate

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the potential of plant alkaloid for repositioning in cancer therapy. Research on plant alkaloids is not only valuable to bring them into the clinics. Knowledge

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gained with investigating these compounds may also be utilized for the generation of derivatives with improved pharmacological features, i.e. improved bioavailability and pharmacokinetics, less resistance

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development and less side effects etc. For instance matrine and oxymatrine are quinazoline alkaloids. Knowledge gained with this alkaloid class may be helpful to synthesize even completely novel quinazoline alkaloids for therapeutic purposes. Several synthetic quinazoline alkaloids entered the clinic during recent years, e.g. afatinib, erlotinib, gefitinib and lapatinib. The further preclinical and clinical development of plant alkaloids should follow the same stringent rules as any synthetic drug as well. What is most required at this point is the conduction of clinical studies to estimate the clinical utility of plant-derived alkaloids. Though preliminary clinical data are available [74, 75], prospective randomized, placebo-controlled clinical Phase I and II trials should 12

be initiated in the years to come to unravel the full potential of plant alkaloids in the drug repositioning process.

Funding Source There were no extramural funds to write this paper.

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Conflict of interest: The authors declare that there no conflict of interest.

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29

Table 1: Pharmacological activity of candidate plant-derived alkaloids for drug repositioning in cancer therapy.

Compound

Pharmacological activity

Protoalkaloids (with exocyclic nitrogen): Capsaicin Irritant, produces sensation of burns Ephedrine Indirect sympathomimetic, direct adrenoreceptor agonist Piperine Bioenhancer, increases secretion, antimicrobial

Source plant

Traditional use of source plants

Capsicum spec. Ephedra sinensis Piper nigrum

Spice

lP

re

-p

Alkaloids with heterocyclic nitrogen: (a) derived from aromatic amino acids Isoquinoline Berberine Antiseptic, reduces blood Coptis alkaloids glucose antiarrhythmic, reduces chinensis cholesterol and lipids antidepressive Berbamine Calcium channel blocker Berberis vulgaris Boldine α-adrenergic antagonist Peumus boldus

Antibacterial, hypoglycemic, gastric-mucous membrane protection, inhibitor of human organic cation transporters

Coptis chinensis

Antitussive, bronchodilatation

Papaver somniferum Nelumbo nucifera

na

Coptisine

ur

Noscapine

Jo

Nuciferine

Palmatine

Papaverine

Dopamine receptor blocker

Against jaundice, dysentery, hypertension, inflammation, and liver-related diseases Antispasmotic

Sanguinarine Na+/K+ ATPase inhibitor

30

TCM: against bronchospasms Spice; buddhistic folk medicine: constipation, insomnia, oral abcesses, toothaches, sunburn, appetiting and digestive activity

ro of

Class

Coptis chinensis Papaver somniferum Sanguinaria canadensis

TCM: Digestive disorders caused by bacterial infections

Liver and gallbladder disorders, jaundice, digestive disorders South-American folk medicine: anticonvulsant, liver and gallbladder disorders, gastrointestinal ailments, dyspepsia TCM: Digestive disorders caused by bacterial infections

Narcotic TCM and Ayurveda: hematemesis, epistaxis, hematuria, diarrhea, cholera, fever, hyperdipsia, diuretic, antidiabetic, antiinflammatory TCM: Digestive disorders caused by bacterial infections Narcotic South-American folk medicine: emetic, against warts, against respiratory ailments

Tetrandrine Quinazoline Matrine alkaloids

Anti-arthritis activity by improvement of Th1/Th2 imbalance Calcium channel blocker κ-opioid and μ-opioid receptor agonist

Oxymatrine

Decreases cardiac ischemia, myocardial injury, arrhythmia and improves heart failure Betaxanthin Indicaxanthin Anti-thalassemic activity alkaloids Ipecacuanha Emetine Anti-protozoal, induces alkaloids vomiting (b) derived from tryptophan Indole Brucine Anti-inflammatory and alkaloids analgesic agent

Evodiamine

Reduces fat uptake

Indole-3carbinol

Anti-malaria, anti-babesiosis

Quinine

Anti-malaria

Harmine, harmaline

MAO inhibitor, hallucinogenic

Stephania tetrandra Sophora flavescens

Antiemetic, diuretic

Sophora flavescens Opuntia ficus-indica Carapichea ipecacuanha

Competitive A2a adenosin receptor antagonist, inhibitor of cAMP degradation Theobromine Diuretic, vasodilatating, relaxing smooth heart muscles Theophylline Non-selective inhibitor of phosphodiesterases, A1 and A2 adenosin receptor antagonist, inhibitor of cAMP degradation

31

Emetic, intentional vomiting after poisoning, nauseant, expectorant, diaphoretic Ayurveda and TCM: against pain and swelling

Cinchona officinalis Tetradium ruticarpum

Peruvian traditional medicine: anti-fever, anti-malaria TCM and Kampo medicine: against abdominal pain, acid regurgitation, nausea, diarrhea, acts dysmenorrheal, antiinflammatory, anti-infective Diet

re

lP

na

Jo

(c) derived from purine Caffeine

TCM: hepatitis, viral myocarditis, gastrointestinal hemorrhage, and skin diseases TCM: hepatitis, viral myocarditis, gastrointestinal hemorrhage, and skin diseases Fruit

Strychnos nux-vomica

-p

Anti-malaria

TCM: against rheumatism and arthritis

Various cruciferous vegetables Cinchona officinalis Peganum harmala, Banisteriopsis caapi

ur

Harmane alkaloids

Cinchonine

Sinomenium acutum

ro of

Sinomenine

Coffea arabica, C. robusta Theobroma spec. Camelia sinensis, C. arabica, Theobroma spec.

Peruvian traditional medicine: anti-fever, anti-malaria Traditional Iranian medicine: carminative, anthelmintic, aphrodisiac, galactagogue, diuretic, emmenagogue, antithrombotic, phlegmatic purgative, and strengthening the vision Beverage

Beverages, Chocolate Beverages, Chocolate

Ayurveda: asthma, bronchitis tuberculosis

Jo

ur

na

lP

re

-p

ro of

Pseudoalkaloids (with exocyclic nitrogen): Steroidal Peiminine Anti-inflammatory, anti-allergic, Fritillaria alkaloids antitussive, expectorant roylei

32

Table 2: Inhibition of tumor growth in vivo and cell cycle effects by plant alkaloids.

Mode of action

Reference

Tumor growth↓, G0/G1 cell cycle arrest, oxidative stress (ROS↑, catalase↑, SOD-2↑), FOXO3a↑ Tumor growth↓, G0/G1 cell cycle arrest, ER-stress response↑ (GRP-78↑, p-ERK↑, p-EIF-2a↑, ATF4↑, GADD-153↑)

Qian et al., 2016 [76] Lin et al., 2013 [77]

Capsaicin

Tumor growth↓, G0/G1 cell cycle arrest, p-PI3K↓, p-AKT↓ Tumor growth↓, G0/G1 arrest, E2F-responsive proliferative genes↓ (cyclin E, thymidylate synthase, Cdc25A, Cdc6), E2F4↑

Zhang et al., 2013 [78] Brown et al., 2010 [79]

Xenograft PANC-1 pancreas Ca Xenograft H69 lung Ca

Capsaicin

ro of

Compound Model Tumor type G0/G1 cell cycle arrest: Capsaicin Xenograft 5637 and T24 bladder Ca Capsaicin Xenograft PANC-1 and SW1990 pancreas Ca

Othotopic MDA-MB-231 Tumor growth↓, G0/G1 cell cycle arrest (cyclin xenograft breast Ca D1↓), HER2↓, ERK↓, KIP-1/p27↑

Capsaicin

Xenograft U 266 multiple myeloma

Tumor growth↓, G0/G1 cell cycle arrest, IL-6induced STAT3 activation↓, JAK1↓, c-SRC↓, STAT3-regulated gene products↓ (cyclin D1, Bcl-2, Bcl-xL, survivin, VEGF)

Berbamine

Xenograft SW480 colorectal Ca Xenograft HCT-116 colon Ca Xenograft U87 glioblastoma Xenograft MDA-MB-231 breast Ca

Tumor growth↓, G0/G1 cell cycle arrest

Sinomenine

Xenograft Hep3B hepatocellular Ca Tetrandrine Xenograft 143 B osteosarcoma Matrine Xenograft Eca-109 esophagus Ca Caffeine Xenograft U87.MG glioblastoma Peiminine Xenograft U251 Glioblastoma S-phase arrest: Sinomenine Xenograft SW1116 colon Ca Evodiamine Xenograft LoVo colon Ca

Jo

ur

Sinomenine

re

Tumor growth↓, G0/G1 cell cycle arrest, RAS-ERK pathway↓ Tumor growth↓, G0/G1 cell cycle arrest, p53↑, p53 acetylation↑, SIRT-1↓ Tumor growth↓, G1/S cell cycle arrest, ROS↑, ATM/Chk-2- and ATR/Chk1-mediated DNA-damage response, p-ERK↑, p-JNK↑, p38 MAPK↑ Tumor growth↓, G0/G1 cell cycle arrest

lP

Sinomenine

na

Coptisine

-p

Capsaicin

Tumor growth↓, G0/G1 cell cycle arrest, PTEN↑, p-PTEN↓, p38 MAPK↑, p-p38 MAPK↑ Tumor growth↓, G0/G1 cell cycle arrest, apoptosis↑ (p53↑, p21↑, Bcl-2/Bid ratio↓) Tumor growth↓, G0/G1 cell cycle arrest (pRB↑)

Thoennissen et al., 2010 [80] Bhutani et al., 2007 [81]

Zhang et al., 2018 [82] Huang et al., 2017 [83] He et al., 2018 [84] Li et al., 2014 [85] Lu et al., 2013 [86]

Tumor growth↓, G0/G1 cell cycle arrest, p-AKT↓, p-GSK-3β↓

Tian et al., 2017 [87] Wang et al., 2014 [88] Ku et al., 2011 [89] Zhao et al., 2018 [90]

Tumor growth↓, CIP-1/p21↓, cyclin D1↓, cyclin E↓, COX-2↓, Tumor growth↓, S-phase cell cycle arrest (cyclin A↓, CDK2↓, Cdc25c↓)

Yang et al., 2016 [91] Zhang et al., 2010 [92]

G2/M cell cycle arrest: 33

Noscapine Emetine Evodiamine Evodiamine

Harmine Harmine

Xenograft GBM157 glioblastoma Xenograft U87 glioblastoma Xenograft HepG2 hepatocellular Ca

Tumor growth↓, mitotic genes↓ (MELK, ASPM, TOP-2A, and FOXM-1b) Tumor growth↓, G2/M cell cycle arrest ( tubulin polymerization↑, cyclin B1↑), p-JNK↑ Tumor growth↓, G2/M cell cycle arrest, IL-6induced STAT3 activation↓, p-JAK2↓, p-Src↓, pERK1/2↓, SHP1↑

Xenograft SGC-7901 gastric Ca Xenograft A549 lung Ca

Tumor growth↓, G2/M cell cycle arrest

Harmaline

Xenograft SGC-7901 gastric Ca Inhibition of tumor growth: Piperine, Syngeneic Sarcoma 180 piplartine

Tumor growth↓, G2/M cell cycle arrest, p53 signaling↑ Tumor growth↓, G2/M cell cycle arrest, pCdc2, p21.pp53, cyclin C↑, p-Cdc25c↓ Tumor growth↓

Syngeneic Hamster Ham- Tumor growth↓ 1 cholangio Ca

Berberine

Xenograft SCC-4 tongue squamous Ca Syngeneic B16 melanoma

Tumor growth↓ Tumor growth at high doses↓, but ↑ at high doses

Xenograft Rat C6 glioma Tumor growth↓

ur

Noscapine

na

lP

Berberine

Berberine

Syngeneic B16LS9 melanoma Sanguinarine Xenograft UM-SCC-22BcFluc head and neck Ca Emetine Xenograft PDX lymphoma Emetine Syngeneic Sarcoma 180, Ehrlich ascites tumor

Jo

Noscapine

Wang et al., 2017 [93] Cai et al., 2014 [94] Paydar et al., 2014 [95] Yang et al., 2012 [96] Visnyei et al., 2011 [97] Wu et al., 2017 [98] Yang et al., 2013 [99]

ro of

Boldine

-p

Berberine

Xenograft HONE1 Tumor growth↓, G2/M cell cycle arrest, EBNA-1↓ nasopharynx Ca Xenograft LoVo colon Ca Tumor growth↓, G2/M cell cycle arrest (cyclin B1↓, Cdc2↓, Cdc25c↓) Xenograft MDA-MB-231 Tumor growth↓, G2/M cell cycle arrest, HSP70↓ breast Ca Xenograft LoVo Colon Ca G2/M cell cycle arrest

re

Berberine

Tumor growth and progression↓ Tumor growth↓

Growth of tumors with MYC rearrangement↓ Tumor growth↓

34

Wang et al., 2015 [100] Dai et al., 2012 [101] Wang et al., 2015 [100] Bezerra et al., 2006 [102] Puthdee et al., 2013 [103] Ho et al., 2009 [104] Letasiová et al., 2005 [105] Landen et al., 2004 [106] Landen et al., 2002 [107] Wang et al., 2016 [108] Aoki et al., 2017 [109] Johnson et al., 1974 [110]

Table 3: Inhibition of tumor growth in vivo and induction of apoptosis by plant alkaloids.

Model Xenograft

Capsaicin, dehydrocapsaicin

Xenograft

Capsaicin

Xenograft

Capsaicin

Xenograft

Capsaicin

Xenograft

Capsaicin

Tumor type HOS osteosarcoma U251 glioma

Mode of action Tumor growth↓, apoptosis↑, ERK1/2↓, p38↓ Tumor growth↓, ROS↑, Ca2+↑, apoptosis↑ (mitochondrial depolarization, cytochrome c release, caspase-3↑, caspase-9↑)

Reference Zhang et al., 2017 [111] Xie et al., 2016 [112]

786-O renal Ca PANC-1 and SW1990 pancreas Ca

Tumor growth↓, apoptosis↑ (FADD↑, Bax↑, Bcl-2↓, caspases-3, -8, -9↑) Tumor growth↓, apoptosis↑

Liu et al., 2016 [113] Lin et al., 2013 [77]

PANC-1 pancreas Ca Orthotopic AsPC-1 xenograft pancreas Ca

Tumor growth↓, apoptosis↑, p-PI3K↓, pAKT↓ Tumor growth↓, thioredoxin↓, p-ASK-1↑, caspase-3↑, PARP cleavage

Zhang et al., 2013 [78] Pramanik and Srivastava, 2012 [114] Tumor growth↓, ROS↑, Ca2+↑, apoptosis↑ Lu et al., (Fas↑, Bax↑, Bcl-2↓, mitochondrial 2010 [115] membrane potential↓, cytochrome c release, caspases↑) Tumor growth↓, apoptosis↑ (PARP Thoennissen cleavage), HER2↓, ERK↓, KIP-1/p27↑ et al., 2010 [80] Tumor growth↓, ROS↑, apoptosis↑ (Bax↑, Zhang et al., Bcl-2↓, mitochondrial depolarization, 2008 [116] survivin↓, JNK activation↑, cytochrome c and AIF release, caspase-3↑)

Xenograft

Capsaicin

Orthotopic MDA-MB-231 xenograft breast Ca

Capsaicin

Xenograft

AsPC-1 pancreas Ca

Capsaicin

Xenograft

U 266 multiple Tumor growth↓, apoptosis↑ (caspase↑), myeloma IL-6-induced STAT3 activation↓, JAK1↓, cSRC↓, STAT3-regulated gene products↓ (cyclin D1, Bcl-2, Bcl-xL, survivin, VEGF)

Bhutani et al., 2007 [81]

Capsaicin

Xenograft

PC-3 prostate Ca

Tumor growth↓, ROS↑, apoptosis↑(mitochondrial membrane potential↓) NB4 leukemia Tumor growth↓, ROS↑, apoptosis↑, pp53↑ Melanoma Tumor growth↓, apoptosis↑ (Bax↑, Bcl2↓, XIAP↑, PARP cleavage, caspases-3 and 9↑), p-JNK↑, p-p38↑, p-ERK-1/2↓

Sánchez et al., 2006 [117] Ito et al., 2004 [118] Yoo et al., 2019 [119]

MDA-MB-231 and BT549 breast Ca

Zhao et al., 2017 [120]

ur

na

lP

re

-p

Capsaicin

Xenograft

Jo

Capsaicin

Colo 205 colon Ca

ro of

Compound Capsaicin

Piperine

Xenograft

Berberine

Xenograft

Berberine

Syngeneic HONE1 nasopharynx Ca

Tumor growth↓, DNA double strand breaks↑, apoptosis↑ (Bax↑, Bcl-2↓, cytochrome c release↑, caspases-3 and 9↑) Tumor growth↓, apoptosis↑, EBNA-1↓

35

Wang et al., 2017 [93]

Xenograft

Berberine

Xenograft

Berberine

Xenograft

Berbamine

Xenograft

SW480 colorectal Ca

Berbamine

Xenograft

Berbamine

Xenograft

SKOV3 ovarian Ca PC-3 prostate Ca

Tumor growth↓, β-catenin↓, caspases-3 and -9↑ Tumor growth↓, apoptosis↑ (mitochondrial dysfunction, Bax/Bcl-2 ratio↑, activation of caspases-3 and -9↑)

Zhang et al., 2018 [124] Zhao et al., 2016 [125]

Berbamine

Xenograft

Xenograft

Tumor growth↓, apoptosis↑ (Fas↑, p53↑, mitochondrial membrane potential↓, caspases-3, -8, -9↑) Tumor growth↓, apoptosis↑ (Bax↑, Bcl2↓, mitochondrial membrane potential↓, cytochrome c release, DNA fragmentation, NFκB↑, caspases-3, -7, -9↑), HSP70↓

Wang et al., 2009 [126]

Boldine

HepG2 hepatocellular Ca MDA-MB-231 breast Ca

Coptisine

Xenograft

Tumor growth↓, miR-122↑, apoptosis↑

Chai et al., 2018 [127]

Coptisine

Xenograft

HepG2 hepatocellular Ca HCT116 colorectal Ca

Coptisine

Xenograft

Noscapine

Xenograft

Noscapine

Xenograft

Noscapine

Xenograft

na

HCT-116 colon Ca HepG2 hepatocellular Ca LoVo Colon Ca BGC823 gastric Ca H460 lung Ca

ur Xenograft

Jo

Noscapine

Nuciferine

Xenograft

A549 lung Ca

Sanguinarine Orthotopic HCT116 xenograft colorectal Ca Sinomenine Syngeneic Murine B16F10 melanoma Sinomenine

Xenograft

Tumor growth↓, apoptosis↑, STAT-3↓

Tsang et al., 2013 [121] Tumor growth↓, p53-dependent Choi et al, apoptosis↑ 2009 [122] Tumor growth↓, apoptosis↑ (Bax↑, Bak↑, Katiyar et Bcl-2↓, Bcl-xL↓, caspase-3↑) al., 2009 [123] Tumor growth↓, apoptosis↑ (p53↑, Bax↑, Zhang et al., Bcl-2↓, PARP cleavage, caspases-3, -8, -9↑) 2018 [82]

U87 glioblastoma

-p

re

Paydar et al., 2014 [95]

Tumor growth↓, apoptosis↑ (Bax↑, Bad↑, Han et al., Bcl-2↓, Bxl-xL↓, XIAP↓, cytochrome c 2018 [128] release, APAF-1↑, AIF↑, caspase-3↑)

lP

C666-1 nasopharynx Ca PC-3 prostate Ca A549 and H1299 lung Ca

ro of

Berberine

Tumor growth↓, apoptosis↑ (caspases↑), RAS-ERK pathway↓ Apoptosis↑ (caspase-3↑, PARP cleavage, Bcl-2/Bax ratio↓)

Huang et al., 2017 [85] Xu et al., 2016 [129]

Apoptosis↑ (Bax↑, Bcl-2↓, cytochrome c release, survivin↓, caspases-3 and -9↑) Apoptosis↑ (Bax↑, cytochrome c release, Bcl-2↓, caspase-3↑, caspase-9↑) Apoptosis↑ (Bax↑, Bcl-2↓, PARP cleavage, caspase-3↑)

Yang et al., 2012 [96] Liu et al., 2011 [130] Jackson et al., 2008 [131] Apoptosis↑ (Bcl-2/Bax↓) Liu et al., 2015 [132] Tumor growth↓, apoptosis↑, p-STRAP↓, p- Gong et al., MELK↓ 2018 [133] Tumor growth↓, apoptosis↑ (caspase-3↑, Sun et al., Bax/Bcl-2 ratio↑), autophagy ↑ (Beclin-1↑, 2018 [134] LC3-II↑, p62↓) Tumor growth↓, apoptosis↑, p53↑, p53 acetylation↑, SIRT-1↓

36

He et al., 2018 [84]

Sinomenine

Xenograft

Hep3B hepatocellular Ca

Sanguinarine Xenograft Tetrandrine

Xenograft

Tetrandrine

Xenograft

Tetrandrine

Xenograft

DU145 prostate Ca 143 B osteosarcoma BGC-823 gastric Ca

Matrine

Xenograft

4T1 breast Ca

Matrine

Xenograft

C1498 leukemia

Matrine

Xenograft

Matrine

Xenograft

Eca-109 esophagus Ca HL-60 leukemia

Matrine

Xenograft

Tumor growth↓, apoptosis↑

Tumor growth↓, apoptosis↑ (Bax↑, Bcl2↓, caspase-3↑) Tumor growth↓, apoptosis↑, WNT/βcatenin signaling↓, VEGF↓ Tumor growth↓, apoptosis↑ (caspase-3↑, PARP cleavage) , autophagy↑ (LC3-II↑, pAKT↓, mTOR↓, p70S6K↓, 4EBP1↓) Tumor growth↓, apoptosis↑ (p53↑, p21↑, Bcl-2/Bid ratio↓) Tumor growth↓, apoptosis↑ (Bcl-2/Bax ratio↑, mitochondrial membrane potential↓, cytochrome c release, caspase3↑), p-AKT↓, p-ERK1/2↓

MNNG/HOS osteosarcoma BxPC-3 pancreas Ca

Tumor growth↓, apoptosis↑ (Bax↑, Bcl2↓, caspases-3, -8, -9↑) Xenograft Tumor growth↓ (PCNA↓), apoptosis↑ (Fas↑, Bcl-2/Bax ratio↓, caspases-3, -8, 9↑) Syngeneic Murine H22 Tumor growth↓, apoptosis↑ (Bax↑, Bclhepatocellular 2↓) Ca Xenograft PC-3 prostate Tumor growth↓, apoptosis↑ (p53↑, Bax↑, Ca Bcl-2↓) Xenograft MNNG/HOS Tumor growth↓, apoptosis↑ (Bax↑, Bclosteosarcoma 2↓, mitochondrial dysfunction, cytochrome c release, caspases-3 and -9↑), p-PI3K↓, pAKT↓

Jo

Matrine

Oxymatrine Oxymatrine

Lu et al., 2013 [86]

Sun et al., 2010 [135] Tumor growth↓, apoptosis↑, PTEN↑, pTian et al., PTEN↓, p38 MAPK↑, p-p38 MAPK↑ 2017 [87] Tumor growth↓, apoptosis↑ (Bax↑, Bak↑, Qin et al., Bad↑, Bcl-2↓, Bcl-xL↓, cytochrome c 2013 [136] release, Apaf-1↑) Tumor growth↓, apoptosis↑, AKT↑, JNK↓, Liu et al., ERK↓ 2011 [137]

ur

Matrine

na

Tetrandrine

Li et al., 2014 [85]

Tumor growth↓, apoptosis↑, survivin↓

lP

Matrine

HepG2 hepatocellular Ca Syngeneic Rat RT-2 glioma Xenograft Colorectal Ca

Tumor growth↓, ROS↑, ATM/Chk-2- and ATR/Chk1-mediated DNA-damage response, p-ERK↑, p-JNK↑, p38 MAPK↑ Tumor growth↓, apoptosis↑ (p21/WAF1/ CIP1 ↑, Bax↑, Bcl-2↓, mitochondrial membrane potential↓, cytochrome c and Omi/HtrA2 release↑, survivin↓, caspases-3, -8,-9,-10↑, PARP cleavage)

ro of

MDA-MB-231 breast Ca

-p

Xenograft

re

Sinomenine

37

Chen et al., 2009 [138] Gu et al., 2018 [139] Xiao et al., 2018 [140] Wu et al., 2017 [141] Wang et al., 2014 [88] Zhang et al., 2012 [142]

Liang et al., 2012 [143] Liu et al., 2010 [144] Ma et al., 2008 [145] Wu et al., 2015 [146] Zhang et al., 2014 [147]

Oxymatrine

Xenograft

Brucine

Xenograft

Cinchonine

Xenograft

Cinchonine

Xenograft

Evodiamine

Xenograft

Evodiamine

Xenograft

Harmine

Xenograft

A549 lung Ca

Harmaline

Xenograft

SGC-7901 gastric Ca

Caffeine

Xenograft

na

Harmine

Jo

ur

U87 glioblastoma

Wu et al., 2017 [98]

Tu et al., 2013 [153] Yang et al., 2013 [99]

Zhang et al., 2010 [92] Ding et al., 2019 [154] Hai-Rong et al., 2019 [155] Tumor growth↓, p53 signaling↑, Dai et al., apoptosis↑ 2012 [101] Tumor growth↓, p21↑, p-p53↑, cyclin C↑, Wang et al., p-Cdc25c↓, Fas/FasL↑, activation of 2015 [100] caspases-3,-8↑ Tumor growth↓, apoptosis↑ (caspase-3↑, Ku et al., PARP cleavage) 2011 [89]

lP

Harmine

Wu et al., 2016 [152]

Tumor growth↓, apoptosis↑ (caspase-3↑, PARP cleavage, p-Bcl-2↑), p-PERK↑, pJNK↑ Syngeneic Murine Lewis Tumor growth↓, apoptosis↑, autophagy↑ lung Ca (LC3-II↑, autophagosome formation↑) Xenograft HepG2 Tumor growth↓, apoptosis↑, IL-6-induced hepatoSTAT3 activation↓, p-JAK2↓, p-Src↓, pcellular Ca ERK1/2↓, SHP1↑ Xenograft LoVo colon Ca Tumor growth↓, apoptosis↑ (caspases-3, 8, -9↑) Xenograft MCF-7 breast Bcl-2↓, Bax↑ Ca Xenograft RT4 bladder Tumor growth↓, apoptosis↑ Ca

re

Evodiamine

A498 renal cell Ca

Ruijun et al., 2014 [149] Jin et al., 2018 [150] Qi et al., 2017 [151]

ro of

Evodiamine

Wu et al., 2014 [148]

-p

Evodiamine

SGC-996 Tumor growth↓, apoptosis↑ (Bax↑, Bclgallbladder Ca 2↓, mitochondrial membrane potential↓, NFκB↓, caspase-3↑) U251 glioma Tumor growth↓, apoptosis↑ (Bax↑, Bcl2↓) HepG2 liver Tumor growth↓, apoptosis↑ (PARP1 Ca cleavage, caspase-3↑) HeLa cervix Ca Tumor growth↓, apoptosis (Bax↑, Bcl-2↓, and A549 lung binding to RING domain of TRAF6) Ca U87 Tumor growth↓, apoptosis↑ (p53↑, pglioblastoma p53↑, PARP cleavage, caspase-3↑, DNA fragmentation↑), p-JNK↑

38

Table 4: Inhibition of tumor growth in vivo and induction of non-apoptotic cells death by plant alkaloids. Mode of action Tumor growth↓, ROS↑, mitochondrial membrane potential↓, non-apoptotic cell death↑ Tumor growth↓, oncosis↑ (cell swelling↑, cytoplasmic vacuoles↑, plasma membrane blebbing↑), autophagy↑ (ATP↓, mitochondrial aerobic respiration↑, p-ERK1/2↑)

Reference Yang et al., 2010 [156]

Tumor growth↓, autophagy↑, AMPK/mTOR/ULK1 pathway↓

Wang et al., 2016 [157]

Xenograft HepG2 hepatocellular Ca Tetrandrine Xenograft THP-1 leukemia Tetrandrine Xenograft AMKL leukemia Tetrandrine Xenograft PML-RARαpositive acute promyelocytic leukemia

Tumor growth↓, pyroptosis↓

Chu et al., 2016 [37]

Tumor growth↓, ROS↑, autophagy↑, differentiation↑, c-MYC↓ Tumor growth↓, ROS↑, autophagy↑, AKT and Notch1 signaling↑ Tumor growth↓, ROS↑, autophagy↑, Notch1 signaling↑

Wu et al., 2018 [158] Liu et al., 2017 [159] Liu et al., 2015 [160]

Tetrandrine Xenograft Huh7 hepatocellular Ca Matrine Xenograft PDAC pancreas Ca

Tumor growth↓, ROS↑, autophagy↑, mitochondrial dysfunction, ERK MAPK↑ Tumor growth↓, autophagy↑, mitochondrial metabolic energy function↓, lysosomal protease↓ Tumor growth↓, Bid-mediated nuclear translocation of AIF, caspase-independent cell death Tumor growth↓, apoptosis↑ (caspase-3↑, Bax/Bcl-2 ratio↑), autophagy ↑ (Beclin-1↑, LC3-II↑, p62↓) Tumor growth↓, ROS↑, autophagy↑ (LC3BII↑), AKT-mTOR pathway↓, JNK pathway↑

Gong et al., 2012 [161] Cho et al., 2018 [162]

Tumor growth↓, apoptosis↑, autophagy↑ (LC3-II↑, autophagosome formation↑) Tumor growth↓, autophagy (p-AMPK↓, p-ULK1↓), p-AKT↓

Tu et al., 2013 [153] Zhao et al., 2018 [90]

Berberine

Xenograft U87 glioblastoma

lP

Berberine

Xenograft HepG2 hepatocellular Ca Sinomenine Syngeneic Murine B16F10 melanoma Sinomenine Xenograft U87 and SF767 glioblastoma Evodiamine Syngeneic Murine Lewis lung Ca Peiminine Xenograft U251 glioblastoma

Jo

ur

na

Matrine

Sun et al., 2018 [38]

ro of

Xenograft Glioma

-p

Berberine

re

Compound Model Tumor type Capsaicin Xenograft T24 bladder Ca

39

Zhou et al., 2014 [163] Sun et al., 2018 [134] Jiang et al., 2017 [164]

Table 5: Inhibition of tumor growth in vivo and angiogenesis by plant alkaloids.

Xenograft

Sanguinarine Syngeneic

Sanguinarine Syngeneic

Sanguinarine Xenograft

Reference Hamsa and Kuttan, 2012 [165] U87 Tumor growth↓, AMPK/mTOR/ULK1 pathway↓ Wang et al., glioblastoma 2016 [157] Pica et al., DHD/K12/TRb Tumor growth↓, angiogenesis↓ 2012 [166] colorectal adeno Ca B16 4A5 Tumor growth↓, angiogenesis↓, p-p44/42 De Stefano et melanoma MAPK, p-AKT al., 2009 [167] A375 Tumor growth↓, angiogenesis↓, p-p44/42 De Stefano et melanoma MAPK, p-AKT al., 2009 [167] Huh7 hepato- Angiogenesis↓ Xiao et al., cellular Ca 2015 [168]

Tetrandrine

Xenograft

Tetrandrine

Syngeneic Rat RT-2 glioma Xenograft PANC-1 pancreas Ca Syngeneic Ehrlich ascites tumor

Oxymatrine Brucine

ro of

Berberine

Mode of action Tumor growth↓, angiogenesis↓ (VEGF↓)

Tumor growth↓, angiogenesis↓ (VEGF↓)

-p

Model Tumor type Syngeneic B16-F10 melanoma

Tumor growth↓, NFκB↓, VEGF↓ Angiogenesis↓, p-VEGFR-2 downstream signaling↓ (SRC, FAK, ERK, AKT, mTOR)

re

Compound Berberine

syngeneic Ehrlich Peritoneal angiogenesis and microvessel ascites tumor density↓, VEGF↓

Evodiamine

Xenograft H22 hepatocellular Ca Xenograft RT4 bladder Ca

Tumor growth↓, angiogenesis↓ (VEGFα↓)

Xenograft A549 lung Ca

Tumor growth↓, angiogenesis↓, p53 signaling↑ Tumor growth↓, VEGF↓, nitric oxide↓

Syngeneic B16-F10 melanoma

Tumor growth↓, VEGFR-2↓

Jo

Harmine

na

Harmine

ur

Harmine

lP

Brucine

Theobromine Xenograft HCV-29-v-raf Angiogenesis↓, VEGF↓ transfectant urothelial cells Theobromine Xenograft Primary VEGF↓ ovarian Ca from patients Theophylline Syngeneic B16-F10 Tumor growth↓, angiogenesis↓ melanoma

40

Chen et al., 2009 [169] Chen et al., 2013 [138] Saraswati and Agarwal, 2013 [170] Agarwal et al., 2011 [171] Shi et al., 2016 [172] Hai-Rong et al., 2019 [155] Dai et al., 2012 [101] Hamsa and Kuttan, 2010 [173] SkopinskaRózewska et al., 1998 [174] Barcz et al., 1998 [175] Menon et al., 2002 [176]

Table 6: Inhibition of tumor growth in vivo and signaling pathways by plant alkaloids.

Compound Model Tumor type Transcription factors: Capsaicin Xenograft 786-O renal Ca Capsaicin Xenograft 5637 and T24 bladder Ca Capsaicin Xenograft PANC-1 and SW1990 pancreas Ca

Mode of action

Reference

Tumor growth↓, c-MYC↑

Liu et al., 2016 [113] Qian et al., 2016 [76] Lin et al., 2013 [77]

Capsaicin

Xenograft H69 lung Ca

Tumor growth↓, E2F4↑

Capsaicin

Xenograft PC-3 prostate Tumor growth↓, PSA promoter/enhancer Ca activation by dihydrotestosterone↓, NFκB activation↓, degradation of IκBα↓, proteasome activity↓

Berberine

Xenograft Colon Ca

Berberine

Syngeneic B16-F10 melanoma

Berberine

Xenograft Pimary Tumor growth↓, NFκB↓, p-IKK↓, p-IκB↓ effusion lymphoma Xenograft MDA-MB-231 Tumor growth↓, NFκB↑ breast Ca Xenograft A549 lung Ca c-MYC↓

-p

Tumor growth↓, RXRα binding Tumor growth↓, NFĸB↓, c-Fos↓, HIF↓

re

Nuciferine

Xenograft THP-1 leukemia Oxymatrine Xenograft PANC-1 pancreas Ca Indicaxanthin Xenograft A375 melanoma Emetine Xenograft GBM157 glioblastoma Brucine Xenograft DLD1 colon Ca Brucine Syngeneic Ehrlich ascites tumor

Jo

ur

na

Tetrandrine

Evodiamine

Brown et al., 2010 [79] Mori et al., 2006 [177]

ro of

Tumor growth↓, p-EIF-2a↑, ATF-4↑

lP

Boldine

Harmine

Tumor growth↓, FOXO3a↑

Tumor growth↓, c-MYC↓ Tumor growth↓, NFκB↓ Tumor growth↓, NFκB pathway ↓ Tumor growth↓, FOXM-1b Tumor growth↓, c-MYC↓, Tumor growth↓, mTOR↓

Xenograft HepG2 Tumor growth↓, NFκB↓ hepatocellular Ca Xenograft Primary lung Tumor growth↓, TWIST-1 degradation, Ca, transgenic TWIST-1 pathway↓ tumors 41

Ruan et al., 2017 [178] Hamsa and Kuttan, 2012 [165] Goto et al., 2012 [179] Paydar et al., 2014 [95] Liu et al., 2015 [132] Wu et al., 2018 [158] Chen et al., 2013 [169] Allegra et al., 2018 [180] Visnyei et al., 2011 [97] Ren et al., 2019 [181] Saraswati and Agarwal, 2013 [170] Guo et al., 2018 [182] Yochum et al., 2017 [183]

Harmine

Syngeneic B16-F10 melanoma

Tumor growth↓, nitric oxide↓, NFκB↓, CREB↓, ATF-2↓

WNT/β - catenin signaling: Berberine Xenograft Colon Ca

Evodiamine Matrine

Xenograft SKOV3 ovarian Ca Xenograft H22 hepato- Tumor growth↓, β-catenin↓ cellular Ca Xenograft 4T1 breast Ca Tumor growth↓, WNT/β-catenin signaling↓

ERK/AKT/JNK signaling: Capsaicin Xenograft HOS osteosarcoma Capsaicin Xenograft 786-O renal Ca Capsaicin Xenograft PANC-1 pancreas Ca Piperine Xenograft Melanoma

Zhang et al., 2017 [111] Tumor growth↓, p38↑, JNK MAPK Liu et al., 2016 pathways↑ [113] Tumor growth↓, p-PI3K↓, p-AKT↓ Zhang et al., 2013 [78] Tumor growth↓, p-JNK↑, p-p38↑, p-ERKYoo et al., 1/2↓ 2019 [119] Glioma Tumor growth↓, glycolysis↓ Sun et al., 2018 [38] BGC-823 Tumor growth↓, AKT/mTOR/p70S6/S6 Yi et al., 2015 gastric Ca pathway↓ [184] SY5Y neuro- Tumor growth↓, PI3K-AKT pathway↓, IL-1↓ Qi et al., 2016 blastoma and [185] CT26 colon Ca Tumor growth↓, AKT-mTOR pathway↓, JNK Jiang et al., U87 and pathway↑ 2017 [164] SF767 glioblastoma MDA-MB-231 Tumor growth↓, ROS↑, ATM/Chk-2- and Li et al., 2014 breast Ca ATR/Chk1-mediated DNA-damage response, [85] p-ERK↑, p-JNK↑, p38 MAPK↑

-p

Xenograft

Berberine

Xenograft

Nuciferine

Xenograft

Sinomenine

Xenograft

Sinomenine

Xenograft

Tetrandrine

Xenograft AMKL leukemia Xenograft Huh7 hepatocellular Ca Xenograft HepG2 hepatocellular Ca Xenograft MNNG/HOS osteosarcoma Xenograft HeLa cervix Ca and A549 lung Ca Xenograft U87 glioblastoma

Oxymatrine Cinchonine

Evodiamine

lP

na

ur

Jo

Tetrandrine

Tumor growth↓, ERK1/2↓, p38↓

re

Berberine

Tetrandrine

Ruan et al., 2017 [178] Zhang et al., 2018 [82] Shi et al., 2016 [172] Xiao et al., 2018 [140]

ro of

Berbamine

Tumor growth↓, β-catenin↓ Tumor growth↓, β-catenin↓

Hamsa and Kuttan, 2010 [173]

Tumor growth↓, ROS↑, AKT and Notch1 signaling↑ Tumor growth↓, ROS↑, autophagy↑, mitochondrial dysfunction, ERK MAPK↑ Tumor growth↓, AKT↑, JNK↓, ERK↓

Liu et al., 2017 [159] Gong et al., 2012 [161] Liu et al., 2011 [137]

Tumor growth↓, p-PI3K↓, p-AKT↓

Zhang et al., 2014 [147] Qi et al., 2017 [186]

Tumor growth↓, AKT ubiquitination↓, pAKT↓ Tumor growth↓, p-JNK↑

42

Wu et al., 2017 [98]

Xenograft A498 renal cell Ca Evodiamine Xenograft HepG2 hepatocellular Ca Harmine Xenograft MCF-7 breast Ca Other signaling pathways: Capsaicin Xenograft U 266 multiple myeloma

Tumor growth↓p-PERK↑, p-JNK↑

Tumor growth↓, IL-6-induced STAT3 activation↓, JAK1↓, c-SRC↓, STAT3regulated gene products↓ (cyclin D1, Bcl-2, Bcl-xL, survivin, VEGF)

Bhutani et al., 2007 [81]

Berberine

Xenograft H1975 lung Ca

Tumor growth↓, SREBP1↓, lipidogenesis↓, ROS/AMPK pathway↑

Fan et al., 2018 [187]

Berberine

Xenograft U87 Tumor growth↓, EGFR-MEK-ERK pathway↓ glioblastoma Allograft Primary intra- Tumor growth↓, hedgehog pathway↓, cranial medu- binding to SMO lloblastoma from Ptch+/−; p53−/− mouse

Tumor growth↓,IL-6-induced STAT3 activation↓, p-JAK2↓, p-Src↓, p-ERK1/2↓, SHP1↑ Tumor growth↓, TAZ,↓ p-ERK↓, p-AKT↓

Wu et al., 2016 [152] Yang et al., 2013 [99] Ding et al., 2019 [154]

ro of

Evodiamine

Berberine Coptisine

na

Papaverine

-p

Xenograft Hepatocellular Ca Xenograft C666-1 nasopharynx Ca Xenograft HCT-116 colon Ca Syngeneic Rat C6 glioma

Tumor growth↓ miR-23a, p53-related tumor suppressive genes p21 and GADD-45α Tumor growth↓, STAT-3↓

Wang et al., 2014 [190] Tsang et al., 2013 [121] Tumor growth↓, RAS-ERK pathway↓ Huang et al., 2017 [83] Tumor growth↓, cAMP phosphodiesterase↓ ChelmickaSchorr et al., 1980; 1984 [191, 192] Tumor growth↓, p53 occupancy on miR-16-2 Zhang et al., promoter↑, mi-16 target genes↓ (Bcl-2, 2019 [193] cyclin D1)

re

Berberine

lP

Berberine

Liu et al., 2015 [188] Wang et al., 2015 [189]

ur

Sanguinarine Xenograft Hepatocellular Ca

Tumor growth↓, p-STRAP↓, p-MELK↓

Oxymatrine

Tumor growth↓, constitutive STAT-5 activation↓, JAK1/2 and c-SRC activation↓, IL-6-induced STAT-5 phosphorylation↓

Jo

Sanguinarine Othotopic HCT116 xenograft colorectal Ca Tetrandrine Xenograft 143 B osteosarcoma Tetrandrine Xenograft PML-RARαpositive acute promyelocytic leukemia Xenograft H1299 lung Ca

Tumor growth↓, PTEN↑, p-PTEN↓, p38 MAPK↑, p-p38 MAPK↑ Tumor growth↓, Notch1 signaling↑

43

Gong et al., 2018 [133] Tian et al., 2017 [87] Liu et al., 2015 [160]

Jung et al., 2019 [194]

Xenograft CAL 27 head Tumor growth↓, DYRK-1A↓ and neck squamous cell Ca

Radhakrishnan et al., 2017 [195]

Theophylline Syngeneic B16 Tumor growth↓, melanogenesis↑, cAMP↓ melanoma Other mechanisms: Capsaicin Xenograft PC-3 prostate Tumor growth↓, proteasome activity↓ Ca Berberine Xenograft SKOV3 Tumor growth↓, hERG-1↓ ovarian Ca

Kreider et al., 1975 [196]

Berberine

Wang et al., 2017 [93] Guo et al., 2019 [198] Li et al., 2018 [199] Qi et al., 2017 [151]

Oxymatrine Cinchonine

Tumor growth↓, TMEM-16A chloride channel inhibition Tumor growth↓, activity of wild-type and mutated EGFR↓ Tumor growth↓, p-TAK-1↓

Tumor growth↓, p-JNK↑, blood brain barrier Wu et al., passage 2017 [98]

Jo

ur

na

lP

re

Evodiamine

Tumor growth↓, EBNA-1↓

Mori et al., 2006 [177] Zhi et al., 2019 [197]

ro of

Matrine

Xenograft HONE1 nasopharynx Ca Xenograft LA795 lung adeno Ca Xenograft HCC827 lung Ca Syngeneic U14 squamous cell Ca, HeLa cervix Ca Xenograft U87 glioblastoma

-p

Harmine

44

Table 7: Inhibition of tumor growth in vivo by various mechanisms by plant alkaloids.

Compound Model Tumor type Regulation of the immune functions: Berberine Xenograft MGC 803 gastric Ca Berberine Syngeneic B16-F10 melanoma Brucine

Mode of action

Reference

Tumor growth↓, IL-8 secretion↓

Li et al., 2016 [200] Hamsa and Kuttan, 2012 [165] Agarwal et al., 2011 [171] Qi et al., 2019 [186]

Tumor growth↓, IL-1β↓, TNF-α↓, GM-CSF↓

Syngeneic Ehrlich ascites TNF-α↓, IL-12↑ tumor Secretion of TNF-α, IFN-γ, and IgG↑

Harmine

Tumor growth↓, proinflammatory cytokines↓, IL-2↑, NFκB↓

Syngeneic Ehrlich ascites Tumor growth↓, innate immune response↑ tumor

-p

Caffeine

HeLa cervix Ca and A549 lung Ca Syngeneic B16-F10 melanoma

ro of

Cinchonine Xenograft

Syngeneic H22 hepatocellular Ca Sinomenine Xenograft SW1116 colon Ca Brucine Xenograft U251 glioma

Tumor growth↓, AA metabolic pathway↓, cPL2↓, COX-2↓, PGE2↓ Tumor growth↓, COX-2↓

lP

Berberine

re

Anti-inflammatory response: Berberine Xenograft UtLM uterine Tumor growth↓, COX-2↓ leiomyoma

na

Stress response: Capsaicin Xenograft

Qian et al., 2016 [76] Lin et al., 2013 [77]

Orthotopic AsPC-1 xenograft pancreas Ca

Tumor growth↓, thioredoxin↓

Xenograft

Tumor growth↓, HSP70↓ Tumor growth↓, ER-stress response↑ (GRP78↑, p-ERK↑, p-EIF-2a↑)

Pramanik and Srivastava, 2012 [114] Paydar et al., 2014 [95] Jin et al., 2018 [150]

Tumor growth↓, aerobic respiration↓, glycolysis

Sun et al., 2018 [38]

Jo

Capsaicin

Boldine

Chuang et al., 2017 [202] Li et al., 2015 [203] Yang et al., 2016 [91] Ruijun et al., 2014 [149]

Tumor growth↓, oxidative stress (ROS↑, catalase↑, SOD-2↑), FOXO3a↑ Tumor growth↓, ER-stress response↑ (GRP78↑, p-ERK↑, p-EIF-2a↑, ATF-4↑, GADD153↑)

Xenograft

5637 and T24 bladder Ca PANC-1 and SW1990 pancreas Ca

ur

Capsaicin

Tumor growth↓, COX-2↓

Hamsa and Kuttan, 2010 [173] Mandal and Poddar, 2008 [201]

MDA-MB-231 breast Ca Cinchonine Xenograft HepG2 hepatocellular Ca Regulation of tumor metabolism: Berberine Xenograft Glioma

45

Berberine

Xenograft

Peiminine

Xenograft

Differentiation: Tetrandrine Xenograft Tetrandrine Xenograft

Tumor growth↓, impaired glycolysis

THP-1 leukemia AMKL leukemia

Tumor growth↓, differentiation↑, ROS↑, MYC↓ Tumor growth↓, differentiation↑, ROS↑

Tumor growth↓, p-GSK-3β↓

Tumor growth↓, differentiation↑, ROS↑ PML-RARαpositive acute promyelocytic leukemia

Wang et al., 2016 [157] Zhao et al., 2018 [90] Wu et al., 2018 [158] Liu et al., 2017 [159] Liu et al., 2015 [160]

Jo

ur

na

lP

re

-p

ro of

Tetrandrine Xenograft

U87 glioblastoma U251 glioblastoma

46

Table 8: Inhibition of invasion and metastasis by plant alkaloids.

Tumor type HCT-116 colorectal Ca Murine 4T1 breast Ca

Mode of action Primary tumor growth in vivo↓, tNOX↑, epithelial markers↓, mesenchymal markers↑ Metastasis in vivo↓, MMP-9↓, MMP-13↓, apoptosis↑ (caspase-3↑), G2/M cell cycle arrest (cyclin B1↓)

Reference Liu et al., 2012 [204] Lai et al., 2012 [205]

Piperine

Syngeneic

Berberine

Xenograft

SGC7901 gastric cancer

Hu et al., 2018 [206]

Berberine

Xenograft

Endometrial Ca

Primary tumor growth in vivo↓, migration and invasion in vitro↓ (MMP-3↓), G0/G1 cell cycle arrest (cyclin D1↓), Myc↓, Wnt5a↓, cytoplasmic β-catenin↓, HNF4α↓, AMPKHNF4α-WNT5A signaling↓ Primary tumor growth, migration, invasion, and metastasis in vivo and in vitro↓, AP-1mediated miR-101 expression↑, COX-2↓, PGE2↓, miR-101/COX-2/PGE2 signaling↓

Berberine

Berberine

Syngeneic / Xenograft Xenograft

4T1 and MDA- Primary tumor growth and lung metastasis in MB-231 breast vivo↓, TGF-β1↓, MMP-2↓, pyroptosis↑ Ca SiHa cervix Ca Primary tumor growth and metastasis in vivo↓, MMP-2↓, uPA↓, reversal of TGFβ1-induced EMT, E-cadherin↑, N-cadherin↓, SNAIL-1↓, angiogenesis↓

Berberine

Xenograft

Berberine

Chu et al., 2016 [209]

Primary tumor growth and migration in vivo↓, binds to VASP Invasion and metastasis↓, COX-2/PGE2JAK2/STAT3 signaling↓, MMP-2↓, MMP-9↓

Su et al., 2016 [210] Liu et al., 2015 [211]

Lung metastasis in vivo↓, HIF-1α/VEGF signaling↓, ID-1↓

Tsang et al., 2015 [212]

Xenograft

Primary tumor growth in vivo↓, migration and invasion in vitro↓, reversal of TGF-β1-induced EMT, E-cadherin↑, vimentin↓, SNAIL-1↓, SLUG↓ Lung metastasis in vivo↓, ERK↓, COX-2↓, AMPK↑ Primary tumor growth and metastasis in vivo↓, ERK1/2↓, NFκB↓, ATF-2↓, CREB↓ (signaling for MMPs)

Qi et al., 2014 [213]

Lymph node metastasis in vivo↓, p-EZRIN↓, filopodia formation↓

Tang et al., 2009 [216]

lP

re

Migration and invasion in vivo and in vitro↓, pyroptosis↑

Jo

Berberine

HepG2 hepato-cellular Ca Xenograft MDA-MB-231 breast Ca Xenograft SW620 and LoVo colorectal Ca Orthotopic MHCC-97L xenograft hepatocellular Ca

na

Berberine

Sun et al., 2018 [38] Chu et al., 2014 [208]

ur

Berberine

Wang et al., 2018 [207]

ro of

Model Xenograft

-p

Compound Capsaicin

Berberine

Syngeneic

Berberine

Syngeneic

Berberine

Xenograft

A549 lung Ca

B16-F10 melanoma B16-F10 melanoma 5-8F nasopharynx Ca

47

Kim et al., 2012 [214] Hamsa and Kuttan, 2012 [215]

Xenograft

U87MG and U251 glioblastoma

Primary tumor growth in vivo↓, migration, stemness, EMT in vitro↓, SOX-2↓, AKT and STAT-3 signaling↓, SLUG↓, angiogenesis, apoptosis↑, G2/M cell cycle arrest

Noscapine

Xenograft

PC3 prostate Ca

Sanguinarine Xenograft

A549 lung Ca

Primary tumor growth and metastasis in vivo↓ Barken et al., 2010 [218] Primary tumor growth in vivo↓, migration in Wei et al., vitro↓, E-cadherin↑, N-cadherin↓, 2017 [219] vimentin↓, SMAD2/3↓, SNAIL↓, p-SNAIL-2↓, FAF-1↑, apoptosis↑, S-phase arrest

Sinomenine

Xenograft

Sinomenine

Xenograft

MDA-MB-231 breast Ca HOS osteosarcoma

Lung metastasis in vivo↓, activation of NFκB and SHh signaling↓ Metastasis in vivo↓, p-CXCR-4↓, p-STAT-3↓, MMP-2↓, MMP-9↓, RANKL↓, osteoclastogenesis↓, S-phase arrest

Song et al., 2018 [220] Xie et al., 2016 [221]

Tetrandrine

Xenograft

SiHa cervix Ca

Primary tumor growth in vivo↓, invasion and migration in vitro↓, MMP-2↓, MMP-9↓

Zhang et al., 2018 [222]

Tetrandrine

Xenograft

HCCLM9 WT Metastasis in vivo↓, EMT-related proteins↓, and HCCLM9 Wnt/β-catenin pathway↓, MTA1↓ ATG7 KO hepatocellular Ca

Zhang et al., 2018 [223]

Tetrandrine

Syngeneic

Matrine

Xenograft

Matrine

Xenograft

Murine 4T1 breast Ca SK-N-PL neuroblastoma DU 145 prostate Ca

Gao et al., 2013 [224] Shen et al., 2018 [225] Chang et al., 2018 [226]

Matrine

Xenograft

-p

re

lP

na

Xenograft

Jo

Matrine

Xenograft

Lung metastasis in vivo↓, p-ERK↓, NF-κB↓, integrin β5↓, ECSM-1↓, IAM-1↓ Primary tumor growth in vivo↓, migration in vitro↓, TBR-3↑, PI3K/AKT activation↓ Proteasomal chymotrypsin-like (CT like) activity↓, reversal of EMT (vimentin↑, Ncadherin↑, E-cadherin↓), G0/G1 cell cycle arrest (c-MYC↓, cyclin B1↓, cyclin D1↓, CDK1↓), apoptosis↑ (Bcl-2↓, Bax↑)

HeLa cervix Ca Primary tumor growth in vivo↓, invasion and migration in vitro↓, MMP-2↓, MMP-9↓, p38 signaling↓, apoptosis↑

Wu et al., 2017 [227]

DU145 and PC3 prostate Ca HT29 colorectal Ca

Primary tumor growth in vivo↓, MMP-2↓, MMP-9↓, p-p65NF-κB↓ Primary tumor growth and metastasis in vivo↓, MMP-2↓, MMP-9↓, p-p38↓

Huang et al., 2017 [228] Ren et al., 2014 [229]

ur

Matrine

Li et al., 2019 [217]

ro of

Nuciferine

Matrine

Xenograft

U2OS osteosarcoma

Primary tumor growth in vivo↓, metastasis in vitro↓, MMP-2↓, MMP-9↓, p50 and p65 nucelar translocation↓, p-IκB-β↓, p-ERK1/2↓

Li et al., 2014 [230]

Oxymatrine

Xenograft

A439 lung Ca

Brucine

Xenograft

LoVo colon Ca

Primary tumor growth in vivo↓, miR-520↑, VEGF↓ Migration in vivo↓, MMP-2↓, MMP-3↓, MMP-9↓, Frizzled-8↓, Wnt5a↓, APC↓, GSNK1A1↓, AXIN-1↓, p-LRP-5/6↓, GSK-3β↓, p-βcatenin↑

Zhou et al., 2019 [231] Shi et al., 2018 [232]

48

Evodiamine

Harmine

Harmine

Caffeine Caffeine

Caffeine

Orthotopic Glioblastoma xenograft Xenograft HepG2 hepato-cellular Ca Xenograft U87 glioblastoma B16-F10 melanoma

Theophylline Xenograft

MeWo melanoma

Zhu et al, 2019 [234] Zhou et al., 2019 [235] Du et al., 2013 [236]

Zhang et al., 2014 [237]

Invasion in vivo↓, cathepsin B↓, p-FAK↓, pERK↓ Primary tumor growth in vivo↓, invasion and migration in vitro↓, AKT signaling pathway↓

Hamsa and Kuttan, 2011 [238] Cheng et al., 2016 [239] Dong et al., 2015 [240]

Survival in vivo↑, migration in vitro↓, IP3R3mediated Ca2+ release↓

Kang et al., 2010 [241]

Lung and liver metastasis in vivo↓, apoptosis↑ Lentini et al., 2000 [242] Primary tumor growth and lung metastasis in Gitelman et vivo↓, natural killer cell activity↑ al., 1987 [243]

Jo

ur

na

lP

Theophylline Syngeneic

Shu et al., 2013 [233]

ro of

Evodiamine

-p

Evodiamine

Syngeneic/ H22 and Metastasis in vivo (H22)↓, fibronectin↓, MMPXenograft HepG2 liver Ca 2↓, lysyl oxidase↓, and cathepsin C↓ in vitro (HepG2) Xenograft TFK-1 cholPrimary tumor growth in vivo↓, invasion and angio Ca migration in vitro↓, IL-6 -induced STAT3 signaling↓, SHP-2↓ Xenograft Colorectal Ca Metastasis in vivo↓, MMP-9↓, NAD+/NADH ratio↑, SIRT-1↑, acetyl-NFκB p65↓ Xenograft MDA-MB-231 Primary tumor growth and lung metastasis in breast Ca vivo↓, MMP-9↓, uPA↓, and uPAR↓, G0/G1 cell cycle arrest (cyclin D1↓, CDK6↓, p27Kip1↓), apoptosis↑ (Bcl-2↓, Bax↑) , pERK↓, p-p38 MAPK↓ Xenograft Gastric Ca Primary tumor growth in vivo↓, migration, invasion and induced apoptosis in vitro↓, COX2↓, PCNA↓, Bcl-2↓, MMP-2↓ Syngeneic B16F-10 Primary tumor growth in vivo↓, invasion and melanoma migration in vitro↓, MMP9↑, ERK↑, VEGF↑

re

Brucine

49

Table 9: Chemoprevention of cancer by plant alkaloids.

Lung carcinogenesis

Capsaicin

Lung carcinogenesis Lung carcinogenesis Hepatocarcinogenesis

Capsaicin Piperine

Piperine

Lung carcinogenesis

Berberine

Colorectal carcinogenesis Hepatocarcinogenesis Lung carcinogenesis

Berberine Evodiamine

Hepatocarcinogenesis Sanguinarine Skin carcinogenesis

Skin carcinogenesis

Jo

Caffeine

Skin carcinogenesis

ur

Caffeine

TNF-α, IL-6, COX-2 and NF-κB

Ananda-kumar et al., 2012 [244]

No statistically significant effect

Teel et al., 1999 [245]

Tumor incidence↓

Jang et al., 1989 [246] Jang et al., 1989 [246] Gunase-karan et al., 2017 [247]

BP-treated Swiss albino mice DMH- and DSStreated rats DEN- plus PBtreated rats Urethanetreated mice

Protein bound carbohydrate levels↓

Selvendiran et al., 2006 [248]

Nuclear and cytoplasmic βcatenin↓ Hepatocyte proliferation↓, iNOS↓, CYP2E1↓, CYP1A2↓ Tumor size and numbers↓, NOTCH3 signaling↓, DNMTsinduced NOTCH3 methylation↑

Wu et al., 2012 [249] Zhao et al., 2008 [250] Su et al., 2018 [251]

DEN-treated rats UVB-lightirradiated SKH1 mice

Unscheduled DNA synthesis↓, GST-P-positive hepatic foci↓ Skin edema↓, skin hyperplasia↓, leukocyte infiltration↓, ROS↓, ODC,↑ PCNA↑, Ki-67↑

Kim et al., 1992 [252] Ahsan et al., 2007 [253]

UVB-lightirradiated SKH1 mice UVB-lightirradiated p53knockout mice UV-irradiated mouse epidermis

ATR/Chk1 pathway↓ (p-Chk1↓), lethal mitosis↑ (cyclin B1↑, caspase-3↑), apoptosis↑ Apoptosis↑, ATR-mediated pChk1↓, lethal mitosis↑ (cyclin B1↑) No effect on tumor incidence

Lu et al., 2011 [254]

na

Caffeine

BP-treated Swiss albino mice Tobaccospecific NKKtreated AJ mice BP-treated female mice DMBA-treated female mice DEN-treated rats

Caffeine, Skin theophylline carcinogenesis Other carcinogenesis models: Berberine Intstestinal carcinogenesis

Tumor incidence↓

ro of

Capsaicin

Reference

Apoptosis↑, pro-oxidant effect↑

-p

chemical carcinogenesis: Capsaicin Lung carcinogenesis

Carcinogenesis Observations induction

re

Tumor entity

lP

Compound

high fat dietTumorigenesis↓, treated verrucomicrobiota in the gut↓, ApcMin/+ mice Akkermansia and short chain fatty acid-producing bacteria↓ 50

Lu et al., 2008 [255] Zajdela and Latarjet, 1978 [256] Wang et al., 2018 [257]

Berberine

Colitis-associated DSS-treated Tumorigenesis↓, EGFR-ERK tumorigenesis ApcMin/+ mice signaling↓ and colonic epithelium hyperproliferation

Li et al., 2017 [258]

Berberine

Colorectal carcinogenesis Lung carcinogenesis Colorectal carcinogenesis

EGF-stimulated EGFR activation A540 lung Ca implantation ApcMin/+ mice

Wang et al., 2013 [259] James et al., 2011 [260] Ma et al., 2018 [261]

Indole-3carbinol

Postate carcinogenesis

TRAMP mice

Harmine

Glioblastoma carcinogenesis

Tumor cell implantation

Jo

ur

na

lP

re

-p

Palmatine

Wu et al., 2012 [262]

ro of

Berberine

ubiquitin ligase CBL ↑ to downregulate EGFR G0/G1 cell cycle arrest, p-AKT↓, pCREB↓, p-MAPK↓ Tumor size and numbers↓, life span↑, dysplasia↓, IL-1α, IL1-β, IL-8, G-CSF, and GM-CSF in the gut↓ cyclin D1↓ and apoptosis↑ (PARP cleavage, p21↑, caspases-3 and 7↑), ARE-luciferase activity↑, NRF-2-mediated genes↑ (NRF-2, NQO-1) Tumorgenicity↓, self-renewal of stem-like cancer cells↓, differentiation↑, apoptosis↑, pAKT↑

51

Liu et al., 2013 [263]

Table 10: In vivo toxicity of plant alkaloids.

Reference Bezerra et al., 2006 [260] Bezerra et al., 2006 [260] Landen et al., 2004 [261]

Landen et al., 2002 [262]

No side effects

Xenograft

AsPC-1 pancreas Ca NB4 leukemia

Capsaicin Piperine

Xenograft

Melanoma

No side effects

Coptisine

Xenograft

No effects on body weight

Noscapine

Xenograft

Sinomenine

Xenograft

Hepatocellular Ca PC3 prostate Ca SW1116 colorectal Ca

Sinomenine

Xenograft

ur

Matrine

Mice

MDA-MB-231 breast Ca LA795 lung Ca

Matrine

Xenograft

Colorectal Ca

Oxymatrine

Xenograft

Jo

No side effects

lP

Xenograft

na

Capsaicin

re

-p

ro of

Compound Model Tumor type Observations Syngeneic tumor transplantation models: Piperine Syngeneic Sarcoma-180 Hepatotoxicity (hepatocyte degeneration, microvesicular steatosis) Piplartine Syngeneic Sarcoma-180 Nephrotoxicity (hydropic changes of the proximal tubular and glomerular epithelium and tubular hemorrhage) Noscapine Syngeneic Rat C6 glioma No toxicity to the duodenum, spleen, liver, and hematopoietic system; no peripheral toxicity, but vasodilatation in brain Noscapine Syngeneic B16-LS9 No toxicity to the spleen, liver, melanoma duodenum, bone marrow, and peripheral blood Quinine Syngeneic Ehrlich ascites Promotion of tumor growth tumor Xenograft tumor transplantation models: Capsaicin Xenograft SW480 Metastasis↑, EMT↑, MMP-2↑, MMPcolorectal Ca 9↑, AKT/mTOR and STAT-3 pathways↑ Capsaicin Orthotopic MDA-MB-231 No side effects xenograft breast Ca

MNNG/HOS osteosarcoma Genotoxic and carcinogenic effects: Capsaicin TRPV1/KO TPA-promoted mice skin carcinogenesis

No toxicity, but reduced body weight No body weight change at low concentrations, but reduced body weight at high concentrations No side effects No effects on body weight No side effects on physical health No effects on body weight and mortality

Castelli et al., 1996 [263] Yang et al., 2013 [264] Thoennissen et al., 2010 [80] Zhang et al., 2008 [116] Ito et al., 2004 [118] Yoo et al., 2019 [119] Chai et al., 2018 [127] Barken et al., 2010 [218] Yang et al., 2016 [91] Li et al., 2014 [85] Guo et al., 2019 [198] Gu et al., 2018 [139] Zhang et al., 2014 [147]

Cocarcinogenic effect, size and number of Hwang et al., skin tumors↑,COX-2↑, EGF activation, p- 2010 [265] EGFR↑ 52

Capsaicin

Mice

N/A

Cecum tumor induction

Transcapsaicin

Mice

N/A

Piperine

Rats

N/A

Weak mutagenicity in in vivo bone marrow micronucleus and chromosomal aberration in human peripheral blood lymphocytes Bioavailability of aflatoxin

Noscapine

Mice

N/A

Sanguinarine Mice

N/A

Glutathione levels in liver and serum biochemistry revealed no evidence of hepatotoxicity through bioactivation in mice

Caffeine

Mice

Oxymatrine

Brucine

-p

Harmine Caffeine

na N/A

ur

Theophylline Mice

N/A

lP

re

Caffeine

Allameh et al., 1992 [268] Fang et al., 2012 [269]

Ansari et al., 2005 [270] Lu et al., 2016 [271]

ro of

Caffeine

DNA damage in blood and bone marrow cells as determined by the comet assay Mice N/A Hepatotoxicity (transaminases↑, alkaline phosphatase↑, malondialdehyde↑, TNFα↑, TRADD↑, p-SAPK/JNK↑) Mice N/A No dermal toxicity upon transdermal administration Mice N/A DNA adduct formation in liver and kidney indicated genotoxicity Mice N/A No effects on mouse oocytes regarding retardation rate and aneuploidy BD2F1 and Breast Mammary gland development↑ C3H mice carcinogenesis indicative of increased tumorigenesis upon DMBA-treatment Mice N/A Sister chromatide exchange↑

Toth and Gannett, 1992 [266] Chanda et al., 2004 [267]

Protection from toxicity: Berberine Mice

Chronic inflammation of the mesenteric arteries, no evidence of carcinogenicity, incidence of breast Ca, hepatocellular adenoma and carcinoma↓

Berberine

Rats

N/A

Protection of gastrointestinal mucosa from acute heavy alcohol consumption, TNFα↓, IL-1β↓, TLR2↓, TLR4↓ Doxorubicin-induced cardiomyopathy↓, survival↑, heart stroke volume↑, myocardial injury↓, apoptosis (caspase3↓, p-AMPKα↓, p-p53↓, Bcl-2↑)

Nuciferine

Xenograft

A549 lung Ca

Nictotine-induced liver injury↓

Oxymatrine

Rats

N/A

Doxorubicin-induced cardiotoxicity↓ (catalase, malonyldialdehyde, superoxide dismutase, glutathione peroxidase and ROS)

Jo

N/A

Chromosomal damage ↑ upon MMS cotreatment

53

Chen et al., 2013 [272] Yamashita et al., 1988 [273] Mailhes et al., 1996 [274] Welsch et al., 1988 [275] Panigrahi et al., 1983 [276] Frei and Venitt, 1975 [277] National Toxicology Program, 1998 [278] Wang et al., 2015 [279]

Liu et al., 2015 [281] Zhang et al., 2017 [282]

Lv et al., 2012 [280]

Mice

N/A

Protection from vinblastine-induced chromosomal aberrations and mitotic index in bone marrow cells

Caffeine

Syngeneic

RT4 bladder Ca Radioprotection, ATM-Chk2-p53-Puma DNA damage-signaling↓, γH2AX↓, p53binding protein 1↓

Geriyol et al., 2015 [283] Zhang et al., 2014 [284]

Jo

ur

na

lP

re

-p

ro of

Caffeine

54