Recent advances in cancer chemoprevention with phytochemicals

journal of food and drug analysis xxx (xxxx) xxx

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Review Article

Recent advances in cancer chemoprevention with phytochemicals Yen-Chun Koh a, Chi-Tang Ho b, Min-Hsiung Pan a,c,d,* a

Institute of Food Sciences and Technology, National Taiwan University, Taipei, 10617, Taiwan Department of Food Science, Rutgers University, New Brunswick, NJ, 08901, USA c Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan d Department of Health and Nutrition Biotechnology, Asia University, Taichung, 41354, Taiwan b

article info

abstract

Article history:

Over the past few decades, phytochemicals widely present in edible plants have exhibited

Received 11 September 2019

compelling positive biological impact on human health, including treating some cancers.

Received in revised form

In some cases, metabolites and artificially modified products of these natural compounds

5 November 2019

have shown better chemopreventive effects than their natural counterparts. Along with

Accepted 6 November 2019

direct chemopreventive strategies using phytochemicals to treat cancer by leading to cell

Available online xxx

cycle arrest, autophagy and apoptosis, natural compounds have been shown to reverse adverse epigenetic regulation, including altering DNA methylation and histone modifica-

Keywords:

tion, modulating miRNA expression, promoting expression of phase II enzyme for detox-

Cancer chemoprevention

ification,

Circadian rhythm

misalignment, and modifying gut microbiota. These have all become part of indirect but

Gut microbiota

effective and novel strategies in cancer prevention using phytochemicals. Therefore, in

Phytochemicals

this review, we are going to summarize some findings of phytochemicals in cancer che-

Epigenetic modification

moprevention via several distinct strategies, both to highlight promising treatments and to

balancing

inflammation

responses,

recovering

circadian

rhythm

from

encourage new ideas for future studies. Copyright © 2019, Food and Drug Administration, Taiwan. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

1.

Introduction to cancer: an overview

According to the latest global cancer data released by International Agency for Research on Cancer (IARC), the estimated global cancer burden has risen to 18.1 million, and there have been up to 9.6 million deaths in year 2018. In terms of

incidence, the major cancer types as surveyed in 2018 are lung cancer, colorectal cancer and female breast cancer, which are ranked at first, second and fifth, respectively, in terms of mortality. Cancer is a leading cause of death in less economically developed countries as well as high-income countries and constitutes an enormous burden on societies and can

* Corresponding author. Institute of Food Science and Technology, National Taiwan University. 1, Sec. 4, Roosevelt Rd., Taipei 10617, Taiwan. E-mail address: [email protected] (M.-H. Pan). http://dx.doi.org/10.1016/j.jfda.2019.11.001 1021-9498/Copyright © 2019, Food and Drug Administration, Taiwan. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article as: Koh Y-C et al., Recent advances in cancer chemoprevention with phytochemicals, Journal of Food and Drug Analysis, http://dx.doi.org/10.1016/j.jfda.2019.11.001

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considerably stress them at the scientific, economic and political levels [1]. Cancer is known as a multi-stage disease that conceptually can be divided into the initiation, promotion, conversion, progression, and lastly, invasion and metastasis stages. Most chemotherapeutic stages target advanced-stage cases, but there are several shortcomings of advanced chemotherapeutic drugs including side effects, price and single-target mechanisms. In terms of single targeting, although it is suggested that single hits are more than sufficient for certain cancers such as leukemias and sarcomas, most cancers require two or more hits, and three hits or more are prescribed in colorectal cancer. Therefore, recent cancer prevention strategies are often described as multi-stage targeting, including the initiation, promotion and progression stages. In fact, there are two-stage model or expanded/multi-stages models being introduced that have successfully described features in cancer development [2]. While discussing multistage diseases like cancer, it is crucial to understanding the effect of environmental carcinogens as initiators or/and acting as promotional agents [3]. Carcinogens can cause tumor initiation genetically and/or epigenetically, i.e., based on changes in gene expression with or without involvement of changes in cellular DNA sequences; both may lead to promotion in expression of oncogenes and/or repression of tumor-suppressing genes. Mutations can be the result of a number of causes, such as DNA damage from infections, UVinduced tissue damage and reactive oxygen species, and DNA adducts can occur as a consequence of overexpression of phase I enzyme and/or down-regulation of phase II enzyme. Epigenetic modification can be caused by DNA methylation, histone modification and miRNA. The cellular microenvironment has become another concern during cancer development. Inappropriate inflammatory responses can be critical at various cancer stages. Pro-inflammatory macrophages (M1) accelerate development of tumor initiation into the promotion and progression stages while anti-inflammatory macrophages (M2) are found to promote tumor growth, angiogenesis and metastasis. Also, the byproducts of metabolism are undeniably another important influence on the cellular microenvironment. However, there are several factors that affect each other, including the metabolic state of the host, gut microbiota composition and the circadian clock. It has been reported that circadian misalignment may lead to spontaneous metabolic disease and re-composition of gut microbiota. Meanwhile, the aftermath of metabolic disorder syndromes like hyperinsulinemia and hyperglycemia can accelerate tumor growth in an insulin- or glucose-rich microenvironment. Furthermore, metabolic issues like fatty liver and cholestasis may lead to circadian rhythm disruption of peripheral tissue, greatly increasing the incidence of carcinogenesis. The overview of the cancer development as abovementioned is presented in Fig. 1. For the purpose of cancer therapy or prevention of cancer progression, cancer drug development has shown it importance to be done imperatively. Preventive strategies have gained interest in spite of some problems with follow-up control and treatment of cancer [4]; it has been demonstrated that carcinogenic pathways can be more successfully disrupted in the early stages of cancer treatment. However,

cancer drug development is a costly and time consuming process that may not promise the efficacy without side effects. Phytochemicals have exhibited their potential to be a part or substituent of cancer drugs, at the same time reduced the cost and the avoided adverse side effects. Moreover, different phytochemicals may play ameliorative role at different or multiple stages during cancer development. For example, the potential underlying mechanisms to inhibit lung cancer and breast cancer via intervention of phytochemical are presented in Fig. 3 and Fig. 4, while the phytochemicals that have been reported to induce cell cycle arrest of various cancer type are presented in Fig. 2.

1.1.

Initiation stage in cancer development

Transformation of normal human cells into malignant ones is known to be driven by multi-step process, due to genetic alterations including mutations, amplifications or deletions, and/or epigenetic changes. These changes may be caused by undesirable chemicals, drugs or damage from radiation or ultraviolet light, a.k.a. (as known as) initiators, which lead to an increased proliferation ability in mutated or epi-mutated cells causing an imbalance between proliferation and cell death [5]. Furthermore, clonal selection for more aggressive behavior may further enhance the invasive ability of mutated cells in terms of destroying non-mutated tissues. Cancer usually occurs when the abovementioned genetic alterations happen to three of the major classes of genes playing key roles in tumor initiation that drive transformation of normal cells into cancer cells, proto-oncogenes, tumor suppressor genes and those involved in DNA repair mechanisms [6]. Mutations can activate expression of oncogenes that accelerate cell proliferation, or, on the other hand, inactivate tumor suppressor genes inhibiting cell death. A similar role is played by oncogene expression throughout the development of most cancers, although it is suggested that the role of oncogenes might not be equal in all tumor cells, which causes different efficacies during different stages of evolution [7]. Alteration of genes involved in DNA repair is highly related to cancer development. Among various DNA damage mechanisms, DNA mismatch repairedeficient and microsatellite instability are common features in some cancers like gastrointestinal cancer, but rarely in cancers like prostate cancer [8]. Cancers develop over time and accumulate a series of mutations that finally produce malignant tumors and each gene affected by mutation contributes to abnormal cell growth, survival and differentiation [9,10]. Besides genomic mutations, epigenetic modification is one of the potential initial steps of cancer development that will be discussed later [11].

1.2. The promotion and progression stage in cancer development Initiator-mutated cells are much more susceptible to promoters that promote cell proliferation and facilitate survival, which ultimately lead to an increased number of mutationcontaining daughter cells. Unlike most initiators that usually covalently bind to DNA, cancer promoters can either interact with receptors or indirectly alter gene expression and promote

Please cite this article as: Koh Y-C et al., Recent advances in cancer chemoprevention with phytochemicals, Journal of Food and Drug Analysis, http://dx.doi.org/10.1016/j.jfda.2019.11.001

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Fig. 1 e An overview of cancer development and the possible strategy for cancer prevention/therapy via intervention of phytochemicals.

Fig. 2 e Mechanisms of G1 and/or G2/M cell cycle arrest induced by phytochemicals in various cancer. Green boxes, phytochemical; grey boxes, microRNA; white boxes, cell cycle related protein.

cell proliferation even without known receptors. Most tumor promoters cause biological and pro-inflammatory effects after application but usually do not result in tumorigenesis without initiators. For instance, tumor promoters like phorbol ester 12O-tetradecanoylphorbol 13-acetate (TPA) is frequently used in two-stage model carcinogenesis [12].

The promotion stage is a lengthy process and seems to be reversible with intervention of drugs and chemopreventive agents, which indicates that the initiation and promotion stages should be the preferential choice for chemopreventive agent intervention. The phase where premalignant lesions develop into invasive cancer, the progression stage, i.e., the

Please cite this article as: Koh Y-C et al., Recent advances in cancer chemoprevention with phytochemicals, Journal of Food and Drug Analysis, http://dx.doi.org/10.1016/j.jfda.2019.11.001

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Fig. 3 e Underlying mechanisms of breast cancer chemoprevention/treatment after phytochemical intervention. Green boxes, phytochemicals; yellow, microRNA; white boxes with green background, up-regulated protein or gene expression; white boxes with orange background, down-regulated protein or gene expression.

Fig. 4 e Underlying mechanisms in lung cancer chemoprevention/treatment after phytochemical intervention. Green boxes, phytochemicals; white boxes with green background, up-regulated protein or gene expression; white boxes with orange background, down-regulated protein or gene expression. Please cite this article as: Koh Y-C et al., Recent advances in cancer chemoprevention with phytochemicals, Journal of Food and Drug Analysis, http://dx.doi.org/10.1016/j.jfda.2019.11.001

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last, neoplastic transformed stage, leads to an increase in tumor size, invasiveness and metastasis capability, due to genetic and phenotypic changes after transformation [13]. Formation of benign polyps, or those that develop into papilloma, occurs during the progression stage and later, spontaneous mutation leads to malignant transformation before developing into metastatic cancer. Identification of biomarkers, including diagnostic, prognostic and predictive biomarkers, is crucial in the early stages of cancers, as the indicators of pathogenic biological processes and the responses after therapeutic interventions [14]. In fact, the biomarkers during progression or metastasis stage could be much different, and documentation of the changes in tumor biology such as receptor status could be informative for prospective implication of cancers that could be easily developed into metastatic cancers, such as metastasized breast cancer [15]. For instance, aggregation of platelets is normally found around tumors, such that the interaction between platelet and cancer cells is pointed out to be essential during tumor progression. Indeed, hypercoagulability in cancer favors tumor growth and metastasis development, which indicating that hemostatic system activation can be promising for cancer prediction [16]. The tumor progression stage is dominated by mutationbearing cells within tumor population, the so-called clonal selection process. This process continues, increases tumor malignancy, and promotes tumor growth throughout the tumor development process [17]. Among various cancers, it is clearer to understand the progression of tumor development from small benign neoplasm to malignant carcinomas via the colon carcinomas developing process. After several rounds of clonal selection, hyperplasia condition will be created to facilitate further rapid cell division uncontrollable, which leads to an increase in size of adenomas/polyps. At this time, the inner part of the tumor gets farther and farther from blood vessels, causing hypoxia and less access to nutrients. Therefore, angiogenesis factors are needed from the tumor itself or surrounding cells to stimulate blood vessel formation. This is the reason why the vascular endothelial derived growth factor (VEGF) has become one of the most well-understood angiogenesis factors, since the overexpression of VEGF can be highly correlated to tumor progression, which makes antiangiogenesis overall and the VEGF signaling pathway specifically attractive anti-cancer targets [18,19]. Presence of abnormal cells (hyperplastic cells) in the inner part change in form due to additional genetic changes, a.k.a. dysplasia which followed by carcinoma in situ/in situ cancer, finally signifies the next stages of cancer [17,20].

1.3. Invasion and metastasis stage in cancer development Proliferative and genetically changed tumor cells eventually spread through basal lamina and surrounding tissues, mainly connective tissues, penetrating and invading other organs [17]. Similar to normal cells, tumor cells are also capable of remodeling surrounding tissue and migrating via the migration pathway thus made. One of the major differences compared to normal cell is that neither single cell migration nor collective cell migration of these tumor cells has a stop

5

signal, which makes migration the physiological prototypes of invasive growth of tumor cells [21]. Furthermore, accumulation of integrin and selectins during cancer progression contributes to metastasis and mediates interaction between tumor cells and surrounding tissues [22]. Elevation in the invasiveness capacity of malignant cells is usually concomitant with metastasis. Cancer cells enter the blood and lymph and metastasize throughout the body and finally, metastases will form at distant sites. It will be noticed that anti-angiogenesis strategy is effective to inhibit metastasis. It is quite controversial whether additional mutations are required when driving invasion and metastasis, or it is just promoted by the epithelialemesenchymal transition (EMT), an understood, normal biological process, which may depend on the cancer type [23,24]. No matter what it is, the fact is that although success rate is relatively low for metastases to seed, grow and colonize into a macroscopic metastasis, these mutated, invasive, metastasized and clonal-selected cancer cells should be very capable of dealing with their new microenvironment. In that case, with the EMT-induced transcription factors (TFs), the tumor cells could be empowered throughout the invasion-metastasis cascade, to survive, invade, circulate and land [23]. However, there are many lesser anti-tumor strategies focusing on anti-metastatic action because compared to initiation and progression stage, as metastasis is lethal and has a much lower survival rate. Nonetheless, in the view of chemoprevention, anti-tumor invasion and metastasis are still striking and imperative. Chen et al. (2019) showed that shikonin (one of naphthoquinone derivatives rich in the dried root of Lithospermum erythrorhizon Sieb. et Zucc. was capable of inhibiting EMT and Triple negative breast cancer (TNBC) metastasis. Shikonin showed a lower IC50 in three different TNBC cell lines (MDAMB-231, 4T1 and MCF-12A) compared to acetylshikonin and b,b-dimethylacrylshikonin. Shikonin also exhibited an inhibitory effect on migration rate and invasion rate in both MDAMB-231 and 4T1, a clue that it might reverse EMT features. An increase in protein expression of E-cadherin and reduction in N-cadherin, vimentin and snail, were seen accompanied with result of immunofluorescence (including F-actin) enhancing the evidence for shikonin-terminated cell migration and invasion capacity. Wnt/b-catenin is known to promote EMT, and shikonin could significantly repress expression of b-catenin but induce the level of p-b-catenin and GSK-3b; this effect could be reversed by using a specific agonist of b-cateninesignaling LiCl. A similar result was obtained in in vivo studies, demonstrating inhibitory effect of metastasis of MDA-MB-231 cells into the lungs with significant reduction in lung metastases, and increase in expression of p-b-catenin, GSK-3b and E-cadherin but a decrease in total b-catenin and vimentin [25]. Besides Wnt/b-catenin signaling and EMT, which promotes metastasis activity, transcription factor NF-kB (nuclear factor kappa light chain enhancer of activated B cells) was suggested to contribute to the metastasis of prostate cancer cells. Miao et al. (2018) demonstrated the anti-metastasis capacity of bakuchiol, a meroterpenoid as a component of Psoralea corylifolia L. by regulating NF-kB signaling in PC-3, prostate cancer cell line. Besides inhibiting PCNA (proliferating cell nuclear antigen) expression, bakichiol exhibited a positive impact in a

Please cite this article as: Koh Y-C et al., Recent advances in cancer chemoprevention with phytochemicals, Journal of Food and Drug Analysis, http://dx.doi.org/10.1016/j.jfda.2019.11.001

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wound-healing assay and transwell assay, accompanied with significant a decrease in MMP-9 (matrix metalloproteinase) expression and enzymatic activity. Phosphorylation levels of p65 and IkBa induced by LPS were suppressed by bakuchiol, including translocation of p65 to the nucleus. It had been reported that sexual hormone receptors might be responsible for NF-kB signaling seen in previous studies, and it was further confirmed that bakuchiol exerted an inhibitory effect on NFkB via receptor AR (androgen receptor) and ERb (estrogen receptor b), to inactivate enzymatic activity of MMP-9 [26].

1.4.

Stem-like cells and cancer stem cells (CSCs) in cancer

The existence of cancer stem cells (CSCs) was investigated early in 1997 by Bonnet and Dick who found a group of leukemic cells that were capable of initiating tumor formation but found to be relatively fewer in number within tumors. Cancer stem cells, namely thought of as normal stem cells, theoretically have self-renewal ability, can divide into daughter cells, and as such keep their identity while the others are able to differentiate into different cancer cell types. Notably, the progenitor daughter cell is capable of dedifferentiate into the cancer stem cell itself, indicating the compelling tumor plasticity (one of the most famous and attractive topic in cancer research) of cancer stem cells [6]. Most importantly and unfortunately, most developed drugs target actively dividing cells, of which most are non-CSC, although cancer stem cell theory has implied the importance of targeting cancer stem cells as an important strategy because CSCs will eventually repopulate the tumor [27]. Besides uncontrolled proliferation, insensitivity to growth suppression, ability to regulate self-survival and differentiation and ability to escape apoptosis, CSCs are also capable of promoting invasion and metastasis, inducing angiogenesis and lymphangiogenesis, and inducing metabolic shift and EMT [28]. It is believed that the area surrounding cancer stem cells provides necessary signals to facilitate the mechanism of self-renewal mechanism of cancer stem cells. For example, aberrant Notch, Wnt and Hedgehog signaling pathways were observed in some cancers, but they are also implicated when normal stem cells self-renew [6]. Moreover, tumor microenvironments may facilitate interconversion between differentiated cancer cell and CSCs [29]. Cancer cells were suggested to acquire their plasticity, or so-called ‘stemness’ during the tumor initiation state, whereas EMT, as mentioned above, are intimately linked to the stem-like gene expression of cancer cells. In other words, although EMT is more often reported to play a role during tumor progression and metastasis, it induces plasticity of cancer cells during the early stage of cancer development once being activated [30]. In fact, among three theories about the origin of cancer stem cells, one suggests that cancer stem cells are the mutated-differentiated cells that dedifferentiate during EMT. There are several studies showing why CSCs are so crucial in cancers but still, there are a lack of therapies and drug targeting them. According to Islam et al. (2019), CSCs are found to be therapy resistant, because they have increased DNA damageerepair activity, detoxifying activity, ROS

scavenging activity and drug efflux. Moreover, they are capable of activating cell survival pathways, as mentioned above, impair apoptotic activity and most importantly, they are quiescent before they are serious enough to be noticed; all of these properties also make them less sensitive to adjuvant chemoradiotherapy [28]. Some promising strategies targeting CSCs including combining differentiation-inducing drugs with drug eliminating differentiated cancer cells, or focusing on destroying the balance of the microenvironment have been proposed but better understanding of CSCs is still needed to provide accurate treatment [31]. Yilmazer (2018) has demonstrated that inducing oxidative stress may be a promising approach against cancer stem cells. By administering H2O2 on different human cancer cell lines, including lung carcinoma cell line (A549), melanoma cell line (G361) and breast cancer cell line (MCF-7), oxidative stress could be induced in response. Cell numbers in all cell lines reduced in G2/M phase and led to apoptosis, including G361 that highly expressed in number of CD117 þ and CD24-/ CD44 þ cells, indicating cancer cells bearing CSCs also generate responses to oxidative stress [32].

2. Leading causes of cancer development and effect of phytochemicals as chemoprevention strategies As mentioned in Section 1, there are numerous adverse causes that might lead to genetic or epigenetic changes upon DNA. In this section, we will discuss some of the potential factors that are widely discussed, which may result in cancer initiation. Furthermore, intervention of phytochemicals as chemoprevention strategies against these tumor-initiating causes in recent studies will be elucidated in this section.

2.1. Issues causing genetic alteration promote cancer development Chemical compounds and some radiation forms (such as ultraviolet radiation or x-rays) are the most discussed mutagens that can cause irreversible and heritable genetic changes or damages in DNA. However, in this part will focus on the oxidative damage, metabolic activation and chemical adducts that are more likely to occur via dietary and environmental factors (Table 1).

2.1.1. Oxidative stress and anti-oxidative activity during cancer development Under assault of free radicals, DNA damage such as singleand double-strand breaks or hydroxylated bases may occur. These radicals could be hydroperoxide, hydroxyl, and superoxide radicals, with/without transition metal ion catalyzation [33]. On the other hand, free oxygen radicals may also form during metabolic activation. For instance, the major causal factor of heterocyclic amine (HCA)-induced DNA damage, might be oxidative stress [34]. Because of this, oxidative stress, which can cause radical formation from oxygen or nitrogen has gained attention after being recognized as a source of mutagens, at the same time, indicated the importance of antioxidants as preventive option.

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Table 1 e The chemopreventive role of phytochemicals and possible regulatory mechanisms in different experiment models. Phytochemicals b-elemene

Experiment model IL-4-induced M2 macrophage polarization in RAW264.7

M2 macrophage conditioned medium-induced metastasis of Lewis cells

Lewis cells

b-eudesmol

Cholangiocarcinoma cell lines CL-6 and HUCC-T1

Asiatic acid

DMH-induced colon carcinogenesis in rat model

Asiatic acid

Lung cancer cell A549

In vivo anticancer activity in mouse xenograft model of LLC cells in C57BL/5J

Possible mechanism involved

Ref.

 Reduction in Arg-1 expression  Increased re-differentiation of IL-4-induced RAW264.7 into M1 phenotype (with iNOS expression)  Decrement in migration and invasion rate  Reduced EMT promoting protein expression (Vimentin and Ncadherin) and increased in Ecadherin  Inhibited proliferation and enhanced radiosensitivity  Inhibited migration and invasion capability  Induced cell cycle arrest at G0/G1 phase  Induced cell apoptosis with increment in Caspase-3/-7 activity  Reduced ACF formation in both proximal colon and distal colon  Reduced protein level or activities of phase I enzymes including cytochrome P450, cytochrome P4502E1, Cytochrome b5, NADPH-cytochrome P450 reductase and NADHcytochrome b5 reductase in both liver and colonic mucosa  Induced protein level or activities of phase II enzymes including GST, DT-diaphorase and UDPGT in both liver and colonic mucosa  Increased mucin content and protected from mast cell inflammation  Inhibited cell proliferation, reduced PCNA and Cyclin D1 protein level  Induced level of Caspase-3, caspase-9, cytochrome c, Bax and suppressed Bcl-2 expression  Increased in the protein level of PARP, cleaved caspase-9 and cleaved caspase-3 in dose- and time-dependent manner  Release of cytochrome c from mitochondrial  Reduced in red/green ratio using JC-1 staining in dose- and timedependent manner showing mitochondrial dysfunction  Elevated intracellular ROS  Tumor inhibited tumor growth without reducing bodyweight and spleen index  Reduced in PCNA level  Increased in optical density in TUNEL assay

[51]

[54]

[59]

[60]

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Table 1 e (continued ) Phytochemicals

Experiment model

Atractylodin

Cholangiocarcinoma cell lines CL-6 and HUCC-T1

Bakuchiol

Prostate cancer cell line, PC-3

Betulinic acid

Breast cancer cell lines MCF-7 and MDA-MB-231

MMTV-PyVTþ/- mammarytumor-prone female

Betulinic acid **combination with APO2

Zebrafish transplanted with MCF-7 cells Liver cancer cell lines, HUH7 and PLC/PRT/5

HUH7 cells injected athymic nude mice, xenograft tumor model Capsaicin

CaCO-2 cultured in fecal water from DMH-induced colonic cancer in Wistar rat DMH-induced colonic cancer in Wistar rat

Possible mechanism involved

Ref.

 Induced cell cycle arrest at G0/G1 phase  Induced cell apoptosis with increment in Caspase-3/-7 activity  Reduced PCNA in both protein and mRNA level  Repressed expression and enzymatic activity of MMP-9  Suppressed migration and invasion capacity  Inhibited phosphorylation of NFkB and IkBa, and the translocation of former to nucleus via sexual hormone receptors AR and ERb  Inhibited colony formation and elevated expression of cleaved PARP  Suppressed aerobic glycolysis (decrement in both RCAR and OCR), reduced expression of LDH-A, c-Myc and p-PDK1/PDK1 and elevated CAV1, LDH-B  Increment of superoxide anion implied the repression of OXPHOS of mitochondrion  Suppressed cancer glycolysis via Cav-1/NF-kB/c-myc pathway  Decreased LDH-A, c-Myc and PDK1 (glycolysis-related protein) and Ki-67  Inhibited breast cancer growth and reduced tumor burden  Elevated expression of Cav-1 in tumor sample  Increased Cav-1 expression  Attenuated c-Myc expression  Anti-proliferation and proapoptosis  Inhibited colony formation  Induced cleavage of Caspase-8/9/ 3  Elevated PARP cleavage  Decrement in Bcl-2 and Mcl-1 mRNA level  Increment in Bad and Bak level  Increased level of DcR1, DcR2, FADD, p73 and p53 in mRNA level, and p53 in protein level  Elevation in p53, DcR1, DcR2 and FADD mRNA level  Reduction in Ki-67 expression  Cell death in TUNEL analysis  Anti-genotoxicity in comet assay

[54]

[26]

[82]

[62]

[58]

 Reduced peripheral blood leukocytes genotoxicity  Reduced proliferation index (Ki67) and apoptosis index (caspase3)  Decreased crypt distortions and depletion of goblet cells

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Table 1 e (continued ) Phytochemicals

Celastrol

Experiment model

Polarization of RAW264.7 into M2-like macrophage after induction of IL-13

Polarization of BMDM into M2like macrophage after induction of IL-13

Crocetin

BALB/c mice being orthotopically injected with 4T1 cells into mammary fat pad Glycolytic cell lines (A549 and Hela)

Durmillone

Hela and MCF-7

Ethyl acetate extract of Radix Scutellariae (consists of baicalein, wogonin and oroxylin)

Human pancreatic cancer cell line (PANC1 and HPDE6-C7)

BxPC3-bearing mice model

Fucosterol

Human lung cancer cell lines (A549 & SK-LU-1)

A549 injected C57BL/6 mice

Gallic acid

TSGH-8301

Possible mechanism involved  Upregulated genes level related to chemical stimulus, apoptosis and tissue development.  Down-sized tumor volume, ACF formation and mucinous adenocarcinoma  Reduced percentage of M2 cell surface marker CD206 positive macrophages  Interfered STAT6 signaling pathway  Reduced percentage of M2 cell surface marker F4/80 and CD206 positive macrophages  Reduced MRC1, Arg1, Fizz1, Mgl2 and CD11c in mRNA level  Reduced number of metastasis tumor from mammary fat pad to lung  Inhibited activity of lactate dehydrogenase (LDH), specifically human homotetrameric isoform 5 of LDH  Induced autophagy with appearance of autophagosomes, increasing expression in Atg7, Beclin1 and LC3-II  Increased apoptosis rates and level of PARP cleavage  Induced cell apoptosis with cleavage of Caspase-3, -8, PARP and Bid  Induced cell autophagy with conversion of LC3-I into LC3-II, degradation of p62  Increased expression autophagy markers (Vps34, Beclin1, Atg5 and Atg7)  Inhibited pI3K/Akt/mTOR pathway to regulate autophagy  Cleavage of caspase 3 and PARP  Increased accumulation of LC3-II and p62 degradation  Induced apoptosis (increment in cleaved caspase-3, Bax and Bcl-2  Triggered cell cycle arrest at G2/ M phase  Decreased expression of Cdc2, cyclin A and cyclin B1  Increased expression of p21 and p27  Inhibited phosphorylation of Raf-1, MEK1/2 and ERK1/2  Inhibited invasion  Reduced tumor weight and tumor volume  Decreased expression of Ki67 and cleaved caspase-3  Reduced expression of FAS and SREBP1  Decreased expression of p-AKT and p-ERK

Ref.

[52]

[80]

[64]

[65]

[55]

[83]

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Table 1 e (continued ) Phytochemicals

Ginsenoside Rk1

Honokiol

Jatamanvaltrate P

Experiment model

MDA-MB-231

MDA-MB-231 injected nude mice Human lung cancer cells viability

Human breast cancer cell lines (MDA-MB-231, MDA-MB-468, MDA-MB-453, MCF-7)

MCF-7 MDA-MB-231, MDA-MB-468, MDA-MB-453 Breast cancer xenograft in BALB/c nude mice model

Lycopene

DMBA-induced MCF-7

Mulberry leave extract

3T3-L1 conditioned mediuminduced HepG2

Nimbolide

MDA-MB-231 and MCF-7 breast cancer cell lines

Possible mechanism involved  Elevated expression of p27 but decreased in CyclinB1, CDK1 and Skp2  Induced ER alpha elevation  Inhibited invasiveness via decrement in gelatinolytic activity of MMP2  Induced cell cycle arrest at M0/ M1 phase  Increased protein level of p21 and p53  Decreased level of cyclin D1 and CDK4  Induced apoptosis via ROS production and mitochondria damage  Increased expression of cleaved caspase-3/-8/-9, Bax and cytochrome, reduced expression of Bcl-2  Inhibited phosphorylation of PI3K, Akt and mTOR via ROS generation  Reduced tumor weight  Activated ER stress  Induced GRP78/p-PERK/p-eIF2a/ CHOP apoptotic signaling pathway, increased expression of cleaved caspase-9 and Bax, reduced Bcl2 level  Inhibited migration  Increased cleavage of PARP and caspase-3/-7/-8/-9  Induced formation of autophagolysosomes and conversion of LC3-I into LC3-II  Arrested at G0/G1 phase  Induced cell cycle arrest at G2/M phase  Reduced tumor volume  Induced tumor LC3 conversion  Increased number of TUNELpositive cells  Reduced DMBA-induced DNA adduct  Suppressed CYP1A1 induction  Inhibited CYP1 enzymes competitively and CYP1B1 in mRNA level  Elevated UGT activity and mRNA level  Reduced expression of p-IkB, pp38 and translocation of NF-kB  Repressed phosphorylation of STAT3  Suppressed p-Akt and p-mTOR expression  Inhibited TNF-a and IL-6activated proliferation-related signal transduction pathway  Induced autophagy (formation of AVO and acidic lysosomal vacuoles) via ROS elevation in mitochondria

Ref.

[53]

[61]

[67]

[42]

[84]

[66]

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Table 1 e (continued ) Phytochemicals

Experiment model

Orientin

DMH-induced colonic lesion

Orientin

DMH-induced colorectal carcinogenesis in Wistar rat fed with high-fat diet

Osthole

Orthotopic pancreatic cancer in mice model

Primary bone marrow cells from mice model induced with IL-4 RAW 264.7 stimulated with IL-4 Oxyresveratrol

DSS-induced colitis in mice

Phloretin

MDA-MB-231

MDA-MB-231 rumor bearing BALB/c nude mice

Polyphenols from Mangifera indica L. pulp

TNF-a treated MCF-12A

Possible mechanism involved  Arrested MDA-MB-231 in G2/M phase and MCF-7 in G0/G1 phase  Increased expression of Bax, cleaved caspase-3 and -9  Reduced Bcl-2 and PCNA  Elevated LC3-II accumulation and Beclin1 expression, p62 degradation  Decreased mTOR expression  Increased in H3K27Ac expression and reduced in HDAC-2 expression  Reduced polyps and ACF formation  Decreased lipid peroxidation and increased antioxidant status  Suppressed phase I enzymes and elevated phased II enzymes  Inhibited cancer cell proliferation  Reduced metastasis CEA and CA 19-9 (tumor markers)  Suppressed PCNA and Ki67 (proliferative markers)  Abrogated inflammatory mast cell  Down-regulated expression of NF-kB, TNF-a, IL-6, iNOS and COX-2  Reduced in pancreatic tumor size and weight  Decreased M2 macrophage (with F4/80 and CD206 markers in CD11bþ cells) in tumor tissue and spleens  Inhibited M2 polarization with reduction in M2 mRNA level (MRC1, CCL22 and TGF-b)  Downregulated phosphorylated STAT6, ERK1/2 and C/EBP b  Decreased iNOS2 and COX-2 expression  Reduced TNF-a, MCP-1 and IL-6 level  Prevented colon shortening  Retained mucin production  Increased GLUT2 expression  Induced G0/G1 phase cell cycle arrest  Elevated protein level of p21, p27, Rb2 and p53  Reduced protein level of Cyclin D1 and Cyclin E1  Inhibited cell migration  Increased expression of E-cadherin and decreased a-SMA, pFAK, p-Src and Paxillin  Elevated protein expression of p53, p21, E-cadherin  Reduced N-cadherin and Vimentin  Inhibited ROS generation

Ref.

[43]

[85]

[50]

[47]

[81]

[46]

(continued on next page)

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Table 1 e (continued ) Phytochemicals

Experiment model

(Gallic acid, hydroxybenzoic acid hexoside, monogalloylglucosides etc.)

MDA-MB231

Resveratrol

Cervix cancer cell line (Hela)

Resveratrol

Lung cancer cell conditioned medium-induced M2 polarization

Co-culture lung cancer cells with macrophages

LLC mouse model

Rosmarinic acid

DMH-induced colon cancer

Possible mechanism involved  Reduced mRNA level of IL-6, IL1b, NF-kB and VCAM  Reduced protein level of NF-kB and p-NF-kB  Decreased mRNA expression of PI3K, Akt and mTOR  Decreased protein level of total and phosphorylated Akt, mTOR, P70S6K and RPS6  Increased expression of miR-126 which negatively correlated to PI3K  Decreased proangiogenic markers (VEGF) in both mRNA and protein level  Reduced protein expression of NF-kB and p-NF-kB  Induced apoptosis/antiproliferation effect (reduced PARP-1, Bcl-2 in both mRNA and protein level, elevated cleavage of Caspase-3 and PARP, increased expression of cytochrome C)  Decreased expression of PI3K, Akt, mTOR and HIF-1a  Increased mRNA expression of PTEN and p-PTEN  Downregulated miR-21  Decreased SOD activity and GSH level (ROS accumulation)  Induced cellular death via mitophagy activation  Impaired glycolytic and OxPhos protein  Inhibited lung cancer cell conditioned medium-induced M2 polarization (decreased IL-10 secretion)  Downregulated M2 markers (MRC1, CCL24, chil3 and Retnla)  Increased M1 phenotype markers (IL-12 and TNF-a)  Inhibited proliferation of lung cancer cells by abrogating HMDM activation  Decreased lung cancer tumor growth and STAT3 activation in cell models  Decreased lung cancer tumor growth and STAT3 activation in LLC mouse model with decrement in Ki-67 expression  Reduction in percentages of F4/ 80 þ macrophages  Reduced M2 markers (IL-10, Arg1 and CD206)  Reduced ACF and tumor incidence  Reduced lipid peroxidation byproducts (LOOH and CD)  Suppressed phase I enzyme activities (CYP450. CYP4502E1, NADPH-CYP450 reductase, NASH cyt b5 reductase, Cyt b5)

Ref.

[38]

[48]

[44]

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Table 1 e (continued ) Phytochemicals

Sanguinarine

Experiment model

Hepatocellular carcinoma cell lines, HepG2 and Huh7

HepG2 xenograft nude mice model

Schisandrin B

DSS-induced ulcerative colitis in mice model

Colitis-associated cancer

Shikonin

Triple-negative breast cancer cell line (MDA-MB-231, 4T1, MCF-12A)

Possible mechanism involved  Elevated phase II enzyme activities (UDPGT, GST and DTD)  Repressed microbial enzyme activities with adverse effect in colon (b-glucuronidase, b-glucosidase, b-galactosidase, mucinase, nitroreductase and sulphatase)  Up-regulated expression of p53  Elevated expression of p53, caspase 3 and 9, and Bax  Decreased expression of COX-2 and Bcl-2  Increased p53 occupancy on miR-16-2 promoter for activation  Upregulated miR-16 expression and downregulated its downstream target cyclin D1 and Bcl2  Inhibited cell proliferation and induced G1 cell cycle arrest  Induced apoptosis with ROS production  Reduced tumor volume and tumor weight  Increased level of miR-16  Decreased expression of CCND1 and Bcl2  Decreased Ki-67 expression  Recovered colon shortening and reduced DAI  Upregulated expression of Ki67, CDK4/CDK6, Bcl-2 and Lgr5  Reduced mRNA and protein level of pro-inflammatory cytokines (IL-6, IL-1b, TNF-a, IL-12 and IL23)  Increased expression of tight junction protein (E-cadherin and Occludin)  Activated FAK and its downstream signaling proteins (p-JNK, p-p38/MAPK, p-Akt and p-ERK)  Diminished OTUs related to inflammation disorder and colon adenocarcinoma progression and restored OTUs disappeared in DSS-treated mice  Reduced tumor burden and elevated survival rate  Decreased mRNA and protein levels of IL-6, TNF-a and IL-1b  Slowed down cell movement in migration assay and terminated invasion capacity.  Upregulated E-cadherin level and downregulated N-cadherin, vimentin and Snail protein expression.  Decreased level of b-catenin and induced p-b-catenin and GSK-3b in cytoplasm but not in nucleus

Ref.

[86]

[75]

[25]

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Table 1 e (continued ) Phytochemicals

Experiment model NOD/SCID mice injected intravenously with MDA-MB231

Silymarin

Human ovarian cancer cell lines, A2780s and PA-1

Thymol

Bladder cancer cell T24

Thymoquinone

DMH-induced colon cancer

Water extract of ginseng and astragalus (consists of ginsenosides (Rg3, Rg1, Rb1 and Re), astragaloside, ononin, formononetin and calycosin-7-glucoside)

THP-1-induced TAMs

LLC-allografted mice model

Ziyang tea polyphenolenriched extract (EGE, Catechin, EGCG, Quercetin and ECG)

MCF-7

Possible mechanism involved  Inhibited metastasis with fewer lung metastases and smaller size of metastatic nodules.  Lower expression in b-catenin and Vimentin with increment of p-b-catenin, GSK-3b and E-cadherin in lung IHC.  Induced cell cycle arrest at G1/S phase  Increased expression of p53, p21, p27 and reduced CDK2  Induced reduction in membrane potential and release of cytochrome C  Increased expression of Bax and cleaved caspase-3/-9  Increased activity of caspase-9  Reduced expression of Bcl-2  Induced cell cycle arrest at G2/M phase  Reduced expression of Cyclin A, Cyclin B1 and CDK2  Elevated expression of p21  Induced intrinsic apoptosis pathways (increased cleaved Caspase-3 and -9  Increased generation of ROS  Decreased level of Bcl-2, Bcl-XL, Mcl-1 while increased Bax, cytosolic cytochrome C and Smac/Diablo  Activated MAPKs and repressed phosphorylation of PI3K/Akt  Reduced oxidative stress  Promote antioxidant enzyme activities  Repressed polarization of TAMs into M2 macrophages  Increased cytokine secretion of IL-12, TNF-a and IFN-g and inhibited IL-10 and TGF-b level  Elevated IL-12 and iNOS while reduced TGF-b, CD206, Arg-1 and IL-10 in mRNA level  Increased iNOS and reduced Arg1 in protein level  Inhibited tumor average volume  Avoided adverse effect of DDP  Elevated IL-12, TNF-a and IFN-g while reduced in IL-10 and TGF-b in cytokine secretion level in blood  Reversed TAMs to M1 with cytokine secretion, mRNA level and protein expression (similar to cell model) in original TAMs.  Induced cell cycle arrest at G0/G1 with elevation in p53 and reduction in CDK2  Increased Bax and reduced Bcl-2 expression  Induced intrinsic apoptosis via increment in caspase-3 and -9 activity  Induced overproduction of ROS

Ref.

[57]

[56]

[36]

[49]

[37]

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1,2-dimethylhydrazine (DMH) is usually used as an initiator of colon cancer model in mice or rats by inducing oxidative stress (Besides DMH, other genotoxic carcinogens that can be applied in rats or mice model include N-diethylnitrosamine (DEN) for liver carcinogenesis, N-methyl-Nnitrosourea (MNU) for stomach, bladder and liver cancer initiation, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) and N-bis (2-hydroxypropyl) nitrosamine (DHPN) as the initiator of lung, thyroid, kidney, bladder and liver carcinogenesis [35].) According to Krah-Harzallah et al. (2013), DMH may promote oxidative damage in erythrocytes via lipid peroxidation enhancement (30%) and antioxidant enzyme activity decrease (up to 35%), which highly reduced erythrocyte count [36]. Some phytochemicals can either act as promising antioxidant agents to scavenge free radicals like superoxide radical anion or promote the activity of antioxidant enzymes, such as glutathione reductase and catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx), which have the function to transform reactive oxygen species (ROS) into less reactive forms. For example, thymoquinone is the component of oil extract from black cumin seed. Notably, it was capable of repaired DMH-induced erythrocyte oxidative stress, haematological abnormalities, which indirectly but effectively reduced tumor incidence via pre-treatment [36]. Li et al. (2016) suggested that polyphenols from Ziyang tea exhibited repressive effect on human breast cancer via a ROSdependent mechanism. After ensuring expression of the cell cycle and apoptosis-related proteins, including elevation in p53 and Bax and reduction in CDK2 and Bcl-2, determination of increases in caspase-3 and caspase-9 activity indicated that it was mitochondrial pathway-involved apoptosis. By diacetate measuring 20 ,70 edichlorodihydrofluorescein (H2DCFDA) fluorescence intensity, it was shown that the mitochondrial-related apoptosis was induced by ROS production, showing that Ziyang tea extracts rich in EGC, Catechin, EGCG, Quercetin and ECG could enhance intracellular oxidative stress of breast cancer cells [37]. Oxidative stress that promotes DNA damage may also retard cancer progression by inhibiting cell growth. Resveratrol, a natural polyphenol found in grape seeds was reported to inhibit proliferation of metastatic cancer cells by reducing activity of anti-oxidative enzyme SOD and content of glutathione (GSH), an essential metabolite of antioxidant system, in turns of ROS accumulation. Besides this, resveratrol may also induce mitophagy, rather than apoptosis, to activate cellular death, which combine with ROS production to impair glycolysis and OxPhos (oxidative phosphorylation) protein and at the same time [38]. Manuka honey, which has gained attention due to its diverse polyphenol and antioxidant properties, was evaluated for its chemopreventive effect on human colon cancer, which revealed that it exhibited synergistic effects with 5fluorouracil (5-FU) by inducing ROS production, suppressing activity of antioxidant enzymes including SOD, catalase, GPx (glutathione peroxidase) and GR (glutathione reductase), and increased apoptosis- and cell cycleerelated gene expression in HCT-116 and Lovo cells. Furthermore, expression of transcription factor Nrf2 and antioxidant enzymes like SOD and HO-1 decreased after combined treatment of Manuka honey and 5-FU, along with reductions in levels of NF-kB and p-IkBa

15

(nuclear factor of kappa light polypeptide gene enhancer in Bcells inhibitor alpha) [39]. Although ROS production could be a causal factor of mutation leading to cancer, it could also be a potential strategy for cancer prevention. It is clear enough to explain the strategy of preventing DNA damage caused by ROS. Meanwhile, reducing antioxidant enzyme expression or inducing ROS production in cancer cells could be effective and promising for cancer prevention/treatment.

2.1.2. Metabolic de-activation: phase I inhibition and phase II enzyme induction reduces incidence of DNA adduct formation after intervention of phytochemicals CYP450 phase metabolizing enzymes play a role in up to 92e96% of xenobiotic drugs/chemical metabolism for clearance in body. However, these biologically inert compounds/procarcinogens upon being bio-activated can lead to development of cancer via cytotoxicity, DNA mutations, cell death and cellular transformation when overexpressed [40]. On the other hand, phase II enzymes are involved in cellular biotransformation, mainly in conjugation catalyzation, such as glutathione S-transferase (GST) and UDP-glucuronosyltransferase (UGT) for detoxification. For instance, conjugation of GSH to phase I metabolic products, including those carcinogenic hydrophobic compounds can generate metabolites with higher solubility for easy detoxification and cell excretion [41]. Wang and Leung (2010) demonstrated that lycopene could significantly reduce ethoxyresorufin-O-deethylase (EROD) activities, which could cause CYP1A1 induction in dimethyl benz [a]anthracene-induced MCF-7 cells. Furthermore, lycopene effectively inhibited CYP1 enzymes in kinetic studies competitively, and at the same time, reduced CYP1B1 mRNA level. On the other hand, lycopene could induce upregulation of detoxification enzyme, phase II enzyme UGT activity, along with mRNA level of UGT1A1 expression [42]. Orientin, a flavonoid, exhibited alleviation of DMH-induced colorectal lesions in colonic mucosa of high fat dietefed Wistar rats. Besides a decreasing occurrence of DMH-induced polyps and ACF (aberrant crypt foci), alteration of phase I and phase II enzyme activities was also observed in colonic and hepatic tissue. Orientin significantly suppressed phase I enzyme activities, including cytochrome P450, cytochrome b5 while in contrast, increased DT-diaphorase (DTD) and GST activities in both the colonic mucosa and hepatic tissues [43]. In 2016, Venkatachalam et al. demonstrated that rosmarinic acid, a naturally occurring polyphenol, exerted chemopreventive efficacy on DMH-induced colon cancer in rats. Intervention of rosmarinic acid reduced tumor incidence and ACF number. Besides the decrease in oxidative stress, by measuring lipid peroxidation byproducts, including thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH) and conjugated dienes (CD), it was suggested that the changes in phase I and phase II enzyme activities might also be the underlying reason. Significant suppression in phase I enzyme activities, which included CYP450, CYP4502E1, NADPH-CYP450 reductase, NADH-cytb5 reductase and Cyt b5 was observed after treatment of rosmarinic acid in the DMH-induced group. In addition, activity of phase II enzyme, GST, DTD and glucuronosyltransferase (UDPGT) were elevated in both liver and colon tissue after treatment. In

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addition, activities of fecal and mucosal bacterial enzymes, bglucuronidase, b-glucosidase, b-galactosidase, mucinase, nitroreductase and sulfatase were measured. All of the activities of these enzymes were significantly elevated after being treated with DMH, but remarkably reduced after supplementation of rosmarinic acid [44]. The effect of gut microbiota and microbial enzymes on cancer development will be discussed in a later section.

2.2. The effect of epigenetic modifications on cancer development and potential of phytochemicals on cancer prevention MicroRNAs (miRNAs), ~22 nucleotides long non-coding RNAs can cause either mRNA degradation or repression, regulating gene expression. Deletion of genetic loci containing miRNA may lead to unwanted expression of oncogenes [45]. On the other hand, induction of certain miRNA could be a potential anti-cancer strategy, although studies showing the possibility of modulating micro-RNA by intervention of phytochemicals are still insufficient. One of the example of miRNA modulation via phytochemicals was demonstrated by Arbizu-Berrocal et al. (2019), who suggested that polyphenols extracted from Mangifera indica L. (mango) could significantly upregulate the expression of miR-126 and down-regulate miR-21 in TNF-aetreated MCF12A non-cancer and MDA-MB231 breast cell lines, respectively. TNF-a treatment in MCF-12A not only lead to increase in pro-inflammatory cytokines (IL-6, IL-1b, NF-kB and VCAM), but also causing clear modifications of PI3K/AKT/mTOR and a decrease in miR-126 expression, crucial in cell proliferation and tumor growth. However, mango polyphenols could effectively reverse the abovementioned effects and the increase of miR-126 was negatively correlated to mRNA expression of PI3K. The effect of mango polyphenols on breast cancer cell MDA-MB231 was pointed out as decreasing expression of metastasis-related protein, VEGF, an increase in cleavage of caspase-3 and PARP (poly ADP-ribose polymerase) and expression of cytochrome C, and an decrease in Bcl-2 (Bcell lymphoma 2). Furthermore, reduction in PI3K, Akt, mTOR, HIF-a and an increase in PTEN were demonstrated as tumor suppressionerelated phenomena observed after treatment of mango polyphenols. Lastly, although miR-126 was not affected in MDA-MB231 cells, a dramatic inhibition in expression of miR-21, a key oncomiR that is widely reported to be overexpressed in various cancer cells although their function is still not clearly elucidated [46]. Another example of a phytochemical that has been introduced as miRNA-regulator is sanguinarine, a plant alkaloid found in the root of Sanguinaria canadensis, as a modulator of miR-16, which is a known tumor suppressor in various human cancers. Zhang et al. (2019) found that sanguinarine exhibited a regulative effect on miR-16 among 140 compounds. It increased expression of miR-16 in hepatocellular carcinoma cell lines, HepG2 and Huh7 but not in Hep3B due to deletion of p53 in Hep3B, which indicating that p53 expression was compulsory in regulation of miR-16. Furthermore, downregulation of miR-16 target genes, cyclin D1 and Bcl-2 was observed. However, surprisingly, only miR-16-2 but not miR16-1 was regulated by sanguinarine with the presence of

p53. Activation of miR-16 by sanguinarine led to cell cycle arrest at G1/S phase, and ROS production had induced apoptosis of hepatocellular carcinoma cell. In a in vivo xenograft nude mice model, a significant reduction in tumor volume and tumor weight was observed, with a relatively higher expression in miR-16, less Ki-67 positive cells and lower expression of cyclin D1 and Bcl-2. These results indicate that phytochemicals are potential regulators of miRNA and can be an effectual cancer chemopreventive strategy if cancer progressionerelated miRNA is modulated, even though the direct interaction between phytochemicals and DNA resulting in production of miRNA is still not clearly understood.

2.3. The relationship between M1/M2 macrophage polarization, inflammation responses and cancer development, and the effect of phytochemicals on macrophage polarization Chronic inflammation is often concomitant with cancer progression, and therefore, the linkage between inflammation and cancer has elicited attention on whether inflammatory factors accelerate or accentuate cancer progression. Among abovementioned carcinogens being used in tumor development models, 1,2-Dimethylhydrazine dihydrochloride (DMH), azoxymethane and methylazoxymethanol (inter-metabolites of DMH) are specific for rodent colorectal tumor induction models. A high-fat diet can also promote tumor development and progression. According to Kalaiyarasu and Manju (2017), orientin efficiently reduces tumor markers contents, including carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19-9), restore histological changes and suppress PCNA and Ki67, the proliferative markers induced by DMH. Notably, orientin also exhibited anti-inflammatory effects in a DMH-induced colorectal carcinogenesis model, including eliminating inflammatory mast cells, down-regulating proinflammatory transcription factors (TF) like NF-kB, cytokines levels such as TNF-a (Tumor necrosis factor) and IL-6, and expression of inflammatory inducible enzymes, like iNOS (inducible nitric oxide synthase) and COX-2 (cyclooxygenase 2). Dextran sodium sulfate (DSS)-induced mouse colitis model is an inflammatory bowel disease (IBD)-induction model of evaluation before IBD-associated colorectal cancer (CRC). Naturally, anti-inflammation has become one of the strategies against inflammation-related cancer. Ramalus mori ethanol extract was found to consist of oxyresveratrol up to 18.2%. The extract could significantly repress the expression of iNOS2 and pro-inflammatory cytokines (TNF-a, MCP-1 and IL-6) levels. In the colon histology, the extract exhibited a positive impact on retaining mucin in colon tissue. Meanwhile, the mRNA expression of MUC2 (Mucin2) and TFF3 (Trefoil factor 3) increased after intervention of the extract in LS 174T goblet cell, indicating that it could induce mucin production, and therefore, reduce the negative effect in DSS-induced colitis mice model [47]. Besides a pro-inflammatory effect, M2 macrophages (a.k.a anti-inflammatory related macrophages) may also elicit negative effect during cancer progression, especially in malignant tumors by enhancing angiogenesis, migration and

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invasion. Sun et al. (2017) showed that resveratrol inhibited M2 polarization of human monocyte-derived macrophages (HMDMs) in tumor conditioned medium (TCM) of lung cancer cells A549, in terms of decreasing IL-10 secretion and increasing IL-12 and TNF-a levels. Moreover, mRNA of M2 markers including MRC1 (mannose receptor C-type 1), CCL24 (Chemokine CeC motif ligand 24), chil3 (Chitinase-like protein 3) and Retnla (Resistin-like molecule alpha/FIZZ1) were downregulated after intervention of resveratrol. Cytokines produced by activated HMDM accelerated proliferation of A549 and H1299, and this negative effect could be reversed by resveratrol, by suppressing IL-10 production. On the other hand, resveratrol also repressed STAT3 (signal transducer and activator of transcription 3) phosphorylation, in turn inhibiting lung cancer cell growth. Similar results were observed in the in vivo Lewis lung cancer mouse model; resveratrol successfully reduced F4/80 positive expressing cells and M2-like activation (lower IL-10, Arg1 (Arginase) and CD206 mRNA level) in the tumors [48]. A water extract of ginseng and astragalus (WEGA) was found to exhibit a regulative effect on macrophage polarization, which could enhance anti-cancer drug efficiency synergistically. The potential beneficial compounds in the water extract were identified as ginsenosides (Rg3, Rg1, Rb1 and Re), astragaloside, ononin, formononetin and calycosin-7glucoside. Intervention with WEGA increased secretion of IL12, TNF-a and IFN-g in TAMs (Tumor-associated macrophages, induced from THP-1), meanwhile reducing the secretion of IL-10 and TGF-b (Transforming growth factor beta) measured in terms of cytokine level, and Arg-1 (Arginase 1) and TGF-b in terms of mRNA level. Protein expression of iNOS significantly increased in conjunction with a reduction in arg-1 level. Cis-diamine dichloro-platinum (DDP) is a widely used anticancer drug with some adverse side-effects which limiting its long-term usage. By regulating macrophage polarization, combination of WEGA and DDP inhibited proliferation of A549 (significant reduction in average tumor volume) without significant weight loss, compared to DDP group. Addition on that, the collective results showed that combined group could significantly increase the level of IL-12, TNF-a and IFN-g (Interferon-g) while reducing cytokine levels of IL-10 and TGF-b in the peripheral blood in LLC-allografted mice model. Similar results were obtained in original TAM in LLCallografted mice, notably with increase of TAM with CD86 and iNOS along with abrogation of CD206 marker [49]. In summary, the above research showed that inhibition of M2 macrophage polarization is obviously an effective strategy to retard cancer progression in the later stages, and, fortunately, phytochemicals can play a major role in the mechanism. Another study by Wang et al. (2018) demonstrated that osthole, a natural member from coumarin family which can be extracted from Cnidium monnieri inhibited pancreatic cancer progression and attenuated tumor-infiltrating M2 macrophages. In the cell model of Panc 02, osthole significantly inhibited cell proliferation and suppressed migration in a wound healing assay. Tumor size and weight were found to be significantly reduced in an animal model, and it was believed to be closely related to changes in tumor microenvironment. Macrophage populations, measured using F4/80 and CD206

17

markers were reduced in the spleen and the infiltration of M2 macrophages was blocked after being treated with osthole. Furthermore, osthole exhibited an inhibitory effect on polarization of mouse primary bone marrow cells into M2 macrophage stimulated with IL-4, along with reduction in expression of MRC1, CCL22 and TGF-b as measured via mRNA levels. Osthole also downregulated STAT6 phosphorylation, phosphorylated ERK1/2 and C/EBP b in IL-4-stimulated RAW264.7 cell model, which promoted M2 polarization in its original counterpart [50]. In 2017, Yu et al. demonstrated a similar inhibitory effect of b-elemene on promoting effect of M2 macrophages in lung cancer. The results showed that conditioned medium collected from IL-13-induced RAW264.7 significantly increased migration and invasion ability of lung cancer cell (Lewis cells) and this adverse effect could be reversed when the M2 macrophages were pretreated with b-elemene. Moreover, protein expressions of vimentin and N-cadherin, which positively related to EMT, markedly increased in lung cancer cells treated with M2 conditioned medium, along with decrease of E-cadherin, and all these EMT markers were attenuated in b-elemene-treated M2 conditioned medium. It was suggested that the effect was due to re-differentiation of macrophages into M1 phenotype, indicated by iNOS expression. On the other hand, b-elemene also exhibited suppressive effects on proliferation, enhanced radiosensitivity of lung cancer cells and inhibited metastasis capability of lung cancer cells [51]. Inhibitory effect of celastrol on cancer metastasis via M2like polarization suppression was demonstrated by Yang et al. (2018). Celastrol effectively reduced CD206 elevation on the cell surface after induction with IL-13 in RAW264.7. Suppressive effect of celastrol on phosphorylation of STAT6 was suggested to be responsible for the polarization. Similar results were obtained in BMDM (bone marrow-derived macrophages), accompanied with decrease in M2 specific genes such as MRC1, Arg1, Fizz1, Mgl2 and CD11c. In an in vivo study, although there was no effect on size of tumor (orthotopically implanted 4T1 tumor cells into mammary fat pad), the number of metastasis to lung was significantly reduced [52]. Macrophage polarization can be a double-edged sword toward tumor development. To be a promising strategy, the role of M1 or M2 macrophages at different stage must be clarified to avoid the opposite effect. Nevertheless, directing macrophage polarization could be an ameliorative strategy.

3.

Major strategies of cancer inhibition

3.1. Cancer prevention or inhibition by phytochemicals via cell cycle arrest Among cancer prevention or therapeutic strategies, controlling the cell cycle or inducing cell cycle arrest is important, as it is useful for cancer cell growth suppression. Furthermore, it has been widely demonstrated that cell cycle arrest is commonly accompanied by triggering apoptosis as consequence of cell death. In this section, some recently discussed phytochemicals that could induce cell cycle arrest will be discussed. Cell cycle arrest at both G0/G1 and G2/M phases

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could effectively lead to anti-proliferative effect of cancer cell and different phytochemicals might induce cell cycle arrest of cancer cells at different phases. Ginsenoside Rk1 exhibited anti-cancer ability in human triple negative breast cancer cell line MDA-MB-231. Significant induction of cell cycle arrest at G0/G1 phase was observed by using flow cytometry, and cell cycle-related proteins were regulated as well, including elevation in p21, p53 and reduction in cyclin D1 and cdk4. Besides this, cellular apoptosis was also induced via mitochondria damage due to ROS generation. In the xenograft model of BALB/c athymic nude mice model injected with MDA-MB-213, tumor size was efficaciously reduced at a concentration of 20 mg/kg/day, which reached the anti-cancer effect of the docetacel positive control [53]. In 2018, Kotawong et al. demonstrated the efficacy of atractylodin and b-eudesmol, the major two isolated compounds from rhizome of Atractylodes lancea, in cholangiocarcinoma; both atractylodin and b-eudesmol induced cell cycle arrest in CL-6 and HUCC-T1 cells at G0/G1 phase, followed by apoptosis, confirmed by an increase in caspase 3/7 activity [54]. Another phytochemical, fucosterol, an important phytosterol prevalent in various plants and algae exhibited antiproliferative effect on cancer cells, and it was recently found to have inhibitory effect on human lung cancer cell lines. Fucosterol triggered apoptosis in SK-LU-1 and A549 cell lines, with significant increase in cleaved Caspase-3 and Bax level and decrease in Bcl-2 expression in a dose-dependent manner. It was further confirmed that fucosterol-treated lung cancer cells were arrested at the G2/M checkpoint by flow cytometry and Western blot analysis, with significant reduction in Cdc2, cyclin A, cyclin B1 and increase in p21 and p27, and it was suggested that the cell cycle arrest was due to inhibitory effect on phosphorylation of Raf-1, MEK1/2 and ERK1/2. In addition, fucosterol also inhibited the invasive ability of lung cancer cells with decrease in expression of MMP-2 and MMP-9. In the xenograft model, inhibition of fucosterol on lung cancer was measured as a decrease in tumor weight and volume, with a decline in expression of Ki67 and an elevated level in cleaved caspase-3 [55]. Thymol, a natural terpenoid compound extracted from Thymus vulgaris, is another compound that induced cell cycle arrest of bladder cancer cell lines T24 at G2/M phase, with reduction in the expression of cell cycle related protein Cyclin A, Cyclin B1 and CDK2, along with increase in protein level of p21. The consequence of cell cycle arrest was confirmed as leading to apoptosis via intrinsic pathway, with significant increase in cleaved caspase-3 and -9 and Bax, accompanied with reduction in Bcl-2, Bcl-XL and Mcl-1, and ROS generation was found its importance to induce apoptosis. Furthermore, the activation of JNK and p38 with inhibition of PI3K/Akt were suggested to involve in the antitumor capacity of thymol [56]. Silymarin, a flavonolignan isolated from Silybum marianum, exhibited the capability of inducing cell cycle arrest and apoptosis in ovarian cancer cell lines A2780s and PA-1. The cells arrested at G1/S phase in time-dependent manner, concomitant with a significant increase in p53, p21 and p27 expression and a reduction in CDK2. Furthermore, a reduction in membrane potential and release of cytochrome C indicated activation of the apoptotic pathway, accompanied with a

reduction in expression of Bcl-2 and an increase in cleaved caspase-3/-9 and Bax [57]. In summary, more phytochemicals were found to exhibit cell cycleearresting capability in various cancers, accompanied by occurrence of apoptosis. It is possible to partially replace anti-cancer drugs to avoid severe side-effects. Other phytochemicals that may induce apoptosis will be briefly introduced in the following section.

3.2.

Phytochemicals induce cancer cell apoptosis

Anti-proliferative and pro-apoptotic effects are widely reported in natural anticancer bioactive compounds to reduce risk of cancer. Some of these phytochemicals could even reduce cell growth effectually in the early stage, such as preneoplastic lesion in colonic cancer. Cell apoptosis normally accompanied with upregulation of pro-apoptotic markers including Bax, cytochrome c, activation of caspase cascade, and/or reduction in anti-apoptotic/pro-survival proteins like Bcl-2 and Bcl-xL. Capsaicin, the major pungent ingredient in chili peppers has exhibited a compelling effect on anti-proliferation and pro-apoptosis in colonic preneoplastic lesions as reported in year 2018. Anti-genotoxic potential in peripheral blood leukocytes was assessed after DMH injection by using the comet assay. DMH treatment resulted in DNA damage that was significant compared to a control group, while receiving capsaicin could conspicuously prevent this damage. Genotoxicity in of CaCO-2 cells in fecal water was in line with the result of leukocyte genotoxic potential, showing that DMH in fecal water could anomalously cause DNA damage in colon cells. Immunoexpression of Ki-67 was significantly increased after being induced by DMH and being reversed when given capsaicin. Furthermore, DMH-induced toxicity also gave rise to crypt distortions, depletion of goblet cells and increased apoptosis, as seen via histopathology and immunostaining caspase-3. Differential gene expression was also seen in the colonic mucosa, showing that capsaicin could induce differential gene expression with/without DMH intervention as responses to chemical stimulus and stress, tissue development and apoptosis. In a mid-term assay of DMH-induced model in rat, capsaicin intervention significantly reduced tumor volume, number of invasive tumors and ACF formation, and there was no mucinous adenocarcinoma when given a high dosage of capsaicin [58]. Two studies reported that asiatic acid exhibited proapoptotic effects in colon cancer and lung cancer. In the first study, asiatic acid exhibited suppressive effect on DMHinduced ACF formation in the proximal and distal colon in a rat model. Using asiatic acid for the entire period was most efficacious, followed by post initiation and at initiation. Proteins in the intrinsic caspase cascade significantly increased in asiatic acidetreated groups, including Caspase-3 and -9, along with pro-apoptotic marker, Bax and Cytochrome C, and Bcl-2 was reduced. Cell proliferationerelated protein expression, i.e., PCNA and cyclin D1, were markedly reduced as compared to a DMH-treated group after being treated by asiatic acid. Argyrophilic nucleolar organizer regions (a biomarker that is directly related to cell proliferation and ribosome biogenesis) was used to evaluate the extent of cell

Please cite this article as: Koh Y-C et al., Recent advances in cancer chemoprevention with phytochemicals, Journal of Food and Drug Analysis, http://dx.doi.org/10.1016/j.jfda.2019.11.001

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proliferation, which showed a significant increase in the DMH group that was reversed after asiatic acid treatment. Moreover, asiatic acid altered xenobiotic metabolizing enzymes in both the liver and colon, which was reduced (in either protein level or activity) in phase I enzyme including cytochrome P450, cytochrome P4502E1, cytochrome b5, NADPHcytochrome P450 reductase and NADH-cytochrome b5 reductase and increased in phase II enzymes, such as GST, DT-diaphorase and UDPGT. Substantial mucus content was found in asiatic acideadministered groups, indicating a protective effect of asiatic acid on mucus secreting cells. Excessive accumulation of mast cells was found in a higher density in supplemented group compared to DMH-exposed group without supplementation [59]. Another study about Asiatic acid demonstrated that Asiatic acid could also induce lung cancer cell death as reported in year 2017. Asiatic acid induced apoptotic cell death and cell cycle arrest in lung cancer cells A549. After evaluation of mitochondrial membrane potential by using JC-1, it showed that mitochondrial membrane potential collapse in a doseand time-dependent manner with asiatic acid treatment. Furthermore, intracellular ROS was assessed by DCFH-DA fluorescence, showing an elevated result in ROS level, and NAC (N-acetylcysteine) was used to double confirm the role of ROS in asiatic acideinduced apoptosis. This showed apoptosis induced by asiatic acid was markedly reduced when intervened with NAC. All these results indicated asiatic acid induced cell death by triggering mitochondrial dysfunction and ROS induction in A549 cells. Besides of increment in PARP, cleaved caspase-9 and cleaved caspase-3, a decrease in cytochrome c expression also indicated release of cytochrome c from mitochondrial. In an in vivo study of a mouse xenograft model of LLC cells in C57BL/6J, asiatic acid did significantly inhibit tumor growth at the tumor inhibition rate of 54% without reduced bodyweight as compared to the group using 5-Flurouracil (5-FU). Anti-proliferation effect was shown by a using TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) assay and PCNA staining of tumor tissue [60]. Honokiol is a representative component of Magnolia officinalis. It has been reported to exhibit inhibitory effect on human lung cancer cell lines A549 and 95-D via activation of the ER stress signaling pathway, which could further trigger the apoptotic pathway GRP78/p-PERK/p-eIF2a/CHOP, resulting in an increase of cleaved caspase-9 and Bax, along with a reduction of Bcl2, in a dose-dependent manner [61]. Another example of phytochemical-induced apoptosis via caspase cascade was reported by Xu et al. (2017), who demonstrated an inhibitory effect of betulinic acid combined with APO2 (TNF-related apoptosis-inducing ligand) on liver cancer progression. Combinations of betulinic acid and APO2 were found to increase the sensitivity of liver cancer cell lines HUH7 and PLC/PRT/5 (known as APO2-resistant cancer cell lines), suppressing proliferation and inducing apoptosis. Cotreatment of betulinic acid and APO2 not only impeded colony formation of HUH7 and PLC/PRT/5 significantly, but also induced apoptosis via Caspase-3 pathway by inducing cleavage of Caspase-8/9/3, accompanied with cleavage of PARP, reduction in mRNA level of Bcl-2 and Mcl-1 and elevation in Bad and Bak. Furthermore, co-treatment of APO2 and betulinic

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acid also induced levels of p73 and p53. On the other hand, an increase in mRNA level of APO2 receptor DcR1 and DcR2 (Dicer 1 and 2 protein) and their downstream signaling component FADD (Fas-associated protein with death domain) were observed with the combination of APO2 and betulinic acid, concluding that activation of p53 might partly involve involved activation of APO2 receptors. In the in vivo experiment, a similar result was observed in HUH7 celleinjected athymic nude mice, with an increasing level of p53, DcR1, FADD and DcR2 mRNA level, concomitant with downregulation of Ki-67 and a significant increase in TUNEL analysis [62]. Inducing cancer cell apoptosis is the most basic, widely used, direct and effective strategy in cancer prevention. Besides, it can be a part or the final result of the chemoprevention strategy. Therefore, the relationship between apoptosis and other strategies and the underlying mechanism, especially activation of certain genes should be further explained in the future.

3.3. Effect of phytochemicals on cancer cell autophagy induction Cell autophagy is known as type II programmed cell death and plays an important role in cancer chemotherapy. It has two roles, one protects cells from environmental stress for survival, while another acts as a pro-death mechanism. For instance, danthron, 1, 8-dihydroxyanthrquinone, isolated from Pheum palmatum exerted a suppressive effect on cancer cell autophagy, which suggested a chemotherapeutic benefit [63]. Nonetheless, autophagy induction is still undeniably considered as a potential strategy for cancer prevention, leading to type II programmed cell death. A study by Yan et al. (2019) suggested that durmillone, a compounds isolated from stems of Millettia pachyloba Drake, showed the best activity among flavonoids that induced autophagy, in both HeLa and MCF-7 cells. A remarkable upregulation in expression of LC3-II, Beclin1 and Atg7 was observed after intervention of durmillone. Durmillone also induced apoptosis, accompanied with PARP cleavage and significant apoptosis rates in dose-dependent manner [64]. Another study showed that an ethyl acetate extract of Radix scutellariae (Scutellaria baicalensis Georgi), which consisted of 62.9% baicalein, wogonin and oroxylin-A, induced autophagy and apoptosis in pancreatic cancer cells, PANC and BxPC3, but such activity was not significant in non-malignant cell line, HPDE6-C7. Besides cleavage of caspase-3, caspase-8, PARP and Bid, which indicated induction of caspase-dependent apoptosis, an increase in conversion of LC3-I into LC3-II was concomitant with degradation of p62 level, elevation of vps34, Beclin1, Atg-5 and Atg-7, which corroborated an occurrence of autophagy. Moreover, it was elucidated that the underlying mechanism was through inhibition of the PI3K/Akt/mTOR/ P70S6K pathway. A suppressive effect of ethyl acetate extract of R. scutellariae on tumor growth was determined in a xenograft model (BxPC3-bearing mice), which resultant in cleavage of Caspase 3 and PARP, accompanied with LC3-II conversion and p62 degradation [65]. Another example of phytochemical-induced autophagymediated cell death was demonstrated by Pooladanda et al.

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(2018) showing that nimbolide, a terpenoid lactone found in Azadirachta indica flowers and leaves, could effectively combat breast cancer. Acidic vesicular organelles (AVO) and acidic lysosomal vacuoles were observed as characteristic of autophagy; nimbolide also induced ROS, causing damage to mitochondria that may result in autophagic cell death, and arrested MDA-MB-231 in phase G2/M while MCF-7 in phase G0/G1. Inhibition of mTOR and up-regulatory effect on LC3A/ B, Beclin1 and degradation of protein p62 explained the occurrence of autophagy. In addition, an increase in Bax, cleaved caspase-3 and -9, along with reduction in Bcl-2 and PCNA confirmed the pro-apoptotic effect of nimbolide on breast cancer. Surprisingly, nimbolide effectively elevated expression of H3K27Ac and resulted in HDAC-2 inhibition, finally leading to activation of breast cancer cell death [66]. Jatamanvaltrate P, an iridoid ester isolated from a traditional medicinal plant, Valeriana jatamansi Jones, induce cell cycle arrest, apoptosis and autophagy in human breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-468 and MDA-MB453). Induction of caspase-dependent apoptosis was observed with increased expression in cleaved PARP and caspase 3/7/8/9, accompanied by a dramatic elevation in most of the above-mentioned breast cancer cells arrested at G2/Mphase, while MCF-7 cells were arrested at the G0/G1 phase. Finally, the evidence of conversion of LC3-I into LC3-II and presence of autophagolysosomes indicated that cell death induced by jatamanvaltrate P was associated with activation of autophagic signaling pathway. Similar results were obtained in the breast cancer xenograft nude mice model. Tumor growth was inhibited with significant expression of LC3-II and elevated number of TUNEL-positive cells in the tumor section of treated mice [67]. Therefore, the occurrence of autophagy may be accompanied by apoptosis and cell cycle arrest when the autophagy of cancer cells is not found as protective mechanism for cancer surviving.

4. Other potential risk factors for cancer development 4.1. Gut microbiota re-composition by phytochemicals and the effect of microbiota on cancer development Microbiota are essential for health due to their beneficial functions, such as vitamin synthesis, nutrient metabolism and production of short-chain fatty acids from fermentation of different peptides and amino acids [68]. It is generally wellunderstood that polysaccharides exhibit a regulative effect on microbiota by acting as a prebiotic or by balancing abnormal microbiota composition, while recent studies point out the impact of phytochemicals on the interaction of gut microbiota and several diseases, including colonic cancer [69]. Luo et al. (2018) showed that Ganoderma lucidum polysaccharides (mainly b-glucan) could significantly reduce mortality in AOM/ DSS-induced mice with colonic cancer by 30% and prevented reduction of colon length by lowering relative abundance of Oscillospira and Desulfovibrionaceae and adipocyte lipolysiserelated gene expression [70]. Another example of the positive effect of polysaccharides on gut microbiota was

demonstrated by Li et al. (2019), showing that polysaccharides from Panax ginseng could significantly reverse the adverse effect of antibiotic-associated diarrhea, restore energy metabolism and recover mucosa [71]. Further, phytochemicals such as dietary phenolic compounds were found to reduce several chronic diseases that may elevate the risk of cancer, including obesity, inflammatory bowel disease (IBD), malnutrition or even colon cancer itself via regulation of gut microbiota composition [72,73]. Some studies did mention that the gut microbiome plays some role in cancers. For instants, Golombos et al. (2018) found that Bacteriodes massiliensis had a higher relative abundance in prostate cancer cases, which could be used as potential biomarkers of prostate cancer pathogenesis, with a relative decrease in Faecalibacterium prausnitzii and Eubacterium rectalie [74]. Moreover, microbiota composition may affect cancer development due to different microbial enzyme functions. For instance, as Venkatachalam et al. stated in 2016, bglucuronidase, b-glucosidase, b-galactosidase, mucinase and nitroreductase from faecal and mucosal bacteria may increase the incidence of tumorigenesis, which could be reversed after intervention of rosmarinic acid. Conjugated toxin/carcinogens glucuronides, or aglycones could be deconjugated by bglucuronidase and b-glucosidase, respectively, which lead to recirculation of the carcinogens in colon, and even enterohepatic recirculation. Methylazoxymethanol, hydrolyzed toxic metabolite of DMH is one of the famous examples of the byproduct of b-glucosidase. Activity of mucinase has been reported that may be positively related to inflammatory responses, and it was found that transformation of colon cell into neoplastic cells might be accompanied with degradation of mucin atop the colonic tissue. Reduction in nitroreductase and sulfatase was also noted in increases of tumor incidence after DMH exposure; the former reduces heterocyclic and aromatic nitro compounds into carcinogenic derivatives while the latter deconjugates sulfated mucins and leads to degradation [44]. Schisandrin B, an abundant bioactive dibenzocyclooctadiene derivative from Schisandra chinensis, also exhibited regulatory effect on gut microbiota of AOM/DSS-induced colitisassociated cancer in mice. Besides recovery in colon length shortening and reduction in disease activity index (DAI), downregulation in Ki67, restoration in CDK4/CDK6, Bcl-2 and Lgr5 (Leucine-rich repeat-containing G-protein coupled receptor 5) expression and a decrease of IL-6, TNF-a, IL-1b mRNA and IL-12 and IL-23 protein levels were also observed in DSSinduced colitis in mice. Furthermore, expression of tight junction protein including E-cadherin and Occludin were maintained by intervention of Schisandrin B, accompanied with activation of FAK and its downstream signaling kinases including p-JNK, pp38/MAPK, p-Akt and p-Erk. In the gut microbiota analysis, intervention of Schisandrin B exhibited a suppressive effect on some operational taxonomic units (OTUs), which are positively correlated to inflammation and colon adenocarcinoma progression and restored those which had diminished by DSS. Furthermore, it was surprisingly found that the pivotal OTUs that might disappear after treatment of Schisandrin B, still existed in Schisandrin Betreated mice when co-housing them with colitis mice, indicating the protective

Please cite this article as: Koh Y-C et al., Recent advances in cancer chemoprevention with phytochemicals, Journal of Food and Drug Analysis, http://dx.doi.org/10.1016/j.jfda.2019.11.001

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effect of Schisandrin B in colitis could be counteracted by microbiota transmission. Positive efficacy of Schisandrin B on DSS/AOM-induced colitis-associated cancer was observed with higher survival rate, reduction in tumors number and pro-inflammatory cytokines (IL-6, TNF-a, IL-1b) in mRNA and protein level and prevention in colon shortening [75]. According to Tian et al. (2019), a diet including Lycium rethenicum improved epithelial barrier integrity with increased expression of ZO-1 (zonula occludens-1), occludin, Muc2, claudin-1 and JAM-A (junctional adhesion molecule-A), which might be due to bacterial metabolites, such as SCFA from SCFA producers like Akkermansia, Odoribacter, Lachnospiraceae and Bifidobacterium [76]. In summary, microbiota can affect cancer development; this may be related to inflammation, toxicant metabolism and integrity of colon barrier, which may lead to absorption of unwanted substances. Therefore, re-composition of microbiota via phytochemical intervention could prevent abovementioned adverse effects, direct or indirectly resulting in cancer prevention.

4.2. Changes in host metabolic state and effect of metabolic disorders on cancer development, and the positive impact after phytochemical intervention Obesity is a metabolic abnormality that may increase risk of multiple diseases including cancers. For instance, breast cancer development is reported to be higher (20e40%) in obese, post-menopausal women. Further, insulin resistance, leptin resistance and high blood glucose are all metabolismrelated health issues having positive correlation to occurrence of cancer [77,78]. The Warburg effect explains the increase in aerobic glycolysis in cancer cells resulting in rapid proliferation rate; glucose uptake could be enhanced by hyperglycemia, which provides a high glucose fuel source for cancer cells [79]. Therefore, for cancer treatment, targeting glycolysis could be a promising strategy. Granchi et al. in 2017 demonstrated antiglycolytic capability of crocetin as a potential strategy for cancer prevention. Crocetin, a derivative of saffron successfully inhibited up to 52% of human homotetrameric isoform 5 of lactate dehydrogenase, in terms of lower lactate production in both glycolytic cancer cell lines (A549 and Hela), which indicated the anti-proliferation ability of crocetin via inhibition of LDH by combating glycose consumption of cancer cells [80]. Research above explains the importance of glucose consumption to cancer cells and therefore glucose transporters (GLUTs) have also become ideal targets for cancer prevention. Wu et al. (2018) demonstrated that apple polyphenol phloretin acted as a specific inhibitor of GLUT2 and led to cell cycle arrest and anti-proliferation in the breast cancer cell line, MDA-MB-231, but not in a normal cell line, MCF-10A. The authors suggested that inhibition of GLUT2 activity by phloretin did lead to compensatory upregulation resulting in higher GLUT2 protein expression. Cell cycle arrest at the G0/G1 phase was observed in flow cytometry and Western blots with elevated expression in p21, p27, Rb2 (retinoblastoma-like protein 2) and p53, along with reduction in Cyclin D1 and Cyclin E1. Phloretin also exhibited inhibitory potential on breast cancer cell migration, evidenced by decrease in

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paxillin, a-SMA (alpha-smooth muscle actin), p-FAK (focal adhesion kinase) and p-Src (proto-oncogene tyrosine-protein kinase) and increase in E-cadherin. An in vivo anti-tumor effect of phloretin was further determined. MDA-MD-231 tumor bearing BALC/c nude mice were given phloretin, resulting in a significant decrease in tumor size and changes in tumor protein expression, including upregulation of p53, p21, and Ecadherin, which are all consistent with cell model, and in addition, decrease in N-cadherin and vimentin level [81]. Betulinic acid, a natural pentacylic terpene that can be isolated from birch bark, exhibited an inhibitory effect on breast cancer malignancies. Butulinic acid showed an inhibitory effect on breast cancer cell lines MCF-7 and MDAMB231 cell growth and colony formation, and induced apoptosis in dose-dependent manner, confirmed by flow cytometry and expression of cleaved PARP. Reduction in glucose uptake and lactate production indicated suppressive effect of betulinic acid on glycolytic activity, and results from extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) had further confirmed that the suppression in aerobic glycolysis were due to repression on mitochondrial oxidative phosphorylation (OXPHOS) chain, resulting in apoptosis. The result had been confirmed by using 3-BrPA, a wellunderstood glycolysis inhibitor. Expression of Cav-1 was found to be elevated after intervention of betulinic acid. Overexpression of Cav-1 resulted in a decrease in ECAR and mediation of glycolytic kinases or glycolysis modulatory molecules, including reduction in LDH-A (lactate dehydrogenase A), c-myc and p-PDK1/PDK1 (phosphoinositide-dependent kinase 1) and slight increase LDH-B (lactate dehydrogenase B) responsible in converting lactate into pyruvate. Significant increase in expression of LDH-A, c-Myc and PDK1 was observed in Cav-1/ mouse model. The finding was ensured by silencing CAV-1 that reversed the suppression of LDH-A, c-Myc, and p-PDK1/PDK1 which induced by betulinic acid. It was further concluded that both betulinic acid administration and Cav-1 mediates expression level of c-Myc via the signaling pathway with inhibition of p-p65/p65, decrease in p-IkBa and increase in IkBa, indicating stabilization of complex p65/IkBa mediated c-Myc expression. Anticancer and anti-glycolytic activities of BA were demonstrated in a mouse breast cancer spontaneous model, resulting in significant control of breast cancer growth and lower tumor burden. Moreover, decreases in LDH-A, c-Myc and PDK1 and lower expression in Ki67 and c-Myc were observed. Surprisingly, betulinic acid also exhibited an inhibitory effect on both breast cancer growth and glycolytic activity in zebrafish transplanted with MCF-7 cells in a lower concentration [82]. Fatty acid storage for energy homeostasis is reported as more important and higher in tumors as compared to normal tissue. It was demonstrated by Liao et al. (2018) that gallic acid could exhibit anti-proliferation and anti-migration effect on bladder cancer cells via downregulation of fatty acid synthase (FAS). With a reduction in FAS and SREBP1 (sterol regulatory element-binding protein 1) protein levels, phosphorylated AKT and ERK were found to be inhibited while ER alpha was induced, indicating that gallic acid had a repressive effect on cell proliferation and fatty acid synthesis. To further confirm that proliferation of bladder cancer was inhibited, expression

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of cell cycleerelated proteins was determined with aa decrease in CyclinB1, CDK1 and Skp2 (S-phase kinaseassociated protein 2) and elevation in p27. Gallic acid also suppressed migration and invasion ability of TSGH-8301 cells with reduction of gelatinolytic activity of MMP2 [83]. Excess energy is usually stored as triglycerides in fat tissue, leading to occurrence of obesity. Secretion of proinflammatory cytokines from obese adipose tissue not only lead to inflammatory response but also can enhance cancer cell growth. For instance, TNF-a and IL-6 were reported to activate proliferationrelated transcription factors NF-kB and STAT3. Chang et al. (2018) suggested that mulberry leaf extract could effectively reverse the pro-proliferative effect of hepatocellular carcinoma cell HepG2 via repression of p-IkB, p-p38, c-jun and transactivation of NF-kB. Besides this, the extract also inhibited expression of p-Akt and p-mTOR. In addition, p-STAT3 was also deactivated by the leaf extract. Lastly, the inhibitory effect on HepG2 proliferation of mulberry leaf extract appeared to be through deactivation of TNF-a and IL-6-activated signaling pathway, evidenced by using specific antibodies [84]. The involvement of metabolism during cancer development could be causal and intricate. However, it is understandable that negative health issues like obesity, hyperinsulinemia, hyperglycemia or hyperleptinemia might exacerbate cancer progression and therefore, regulating health status via phytochemicals is a potential strategy rather than focusing on cancer treatment without concerning etiological issue that may widely dysregulate body function.

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10] [11] [12]

[13]

5.

Conclusion

In conclusion, cancer development is a complicated process and there are numerous factors involved. Intervention with phytochemicals, either when used alone or as synergistically, may exert positive effects on cancer chemoprevention. However, the effect of phytochemicals on cancer progression should be clearly defined in future studies.

[14] [15]

[16]

[17]

Declaration of Competing Interest All authors declare that there are no conflicts of interest.

Acknowledgements

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[19]

[20]

This study was supported by the Ministry of Science and Technology [108-2320-B-002-016-MY3, 108-2321-B002-020, 108-2622-B-002-007-CC2]. [21]

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