Potential Mechanisms of Action of Dietary Phytochemicals for Cancer

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Potential mechanisms of action of dietary phytochemicals for cancer prevention by targeting cellular signaling transduction pathways HONGYU CHEN, and Rui Hai Liu J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.7b04975 • Publication Date (Web): 02 Mar 2018 Downloaded from http://pubs.acs.org on March 3, 2018

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Journal of Agricultural and Food Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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Journal of Agricultural and Food Chemistry

Survival factors

Cytokines Wnt

Growth factors

Growth factor receptor

PI3K JAK

Raf NF-κB MEK

GSK3β

STAT β-catenin

c-Jun c-Fos

Bcl-2

Bax

Frizzled

Akt

Ras

MAPK

Cytokine Receptor

RTK

Gene Regulation Cytochrome C Casepase9 Casepase3

Apoptosis

Anti-proliferation

ACS Paragon Plus Environment


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Potential mechanisms of action of dietary phytochemicals for cancer prevention by targeting cellular

2

signaling transduction pathways

3 4

‡

Hongyu Chen†, and Rui Hai Liu†*

5 6 7 8

†

Department of Food Science, Cornell University, Ithaca, NY 14853-7201

‡

Institute of Edible Fungi, Shanghai Academy of Agriculture Science, Shanghai 201403, China

9

10 11

*Address correspondence to this author at Department of Food Science, 245 Stocking Hall, Cornell University, Ithaca, NY 14853-7201 Telephone: 607-255-6235 Fax: 607-254-4868 e-mail: [email protected] ; ORCID ID

12

0000-0002-7018-7929

13

1


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Abstract: Cancer is a severe health problem that significantly undermines life span and quality. Dietary

15

approach helps provide preventive, non-toxic and economical strategies against cancer. Increased intake of

16

fruits, vegetables and whole grains are linked to reduced risk of cancer and other chronic diseases. The

17

anti-cancer activities of plant-based foods are related to the actions of phytochemicals. One potential

18

mechanism of action of anti-cancer phytochemicals is that they regulate cellular signal transduction pathways

19

and hence affects cancer cell behaviors such as proliferation, apoptosis and invasion. Recent publications have

20

reported phytochemicals to have anti-cancer activities through targeting a wide variety of cell signaling

21

pathways at different levels, such as transcriptional or post-transcriptional regulation, protein activation and

22

intercellular messaging. In this review, we discuss major groups of phytochemicals and their regulation on cell

23

signaling transduction against carcinogenesis via key participators, such as Nrf2, CYP450, MAPK, Akt,

24

JAK/STAT, Wnt/β-catenin, p53, NF-κB, and cancer-related miRNAs.

25 26

Keywords: phytochemicals; cancer; carcinogenesis; cellular signal transduction pathways

27

2



28

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Introduction

29 30

Cancer is a severe health problem that significantly undermines life span and quality. According to the World

31

Cancer Report by WHO (world health organization), cancer is viewed as a major contributor to morbidity and

32

mortality, with approximately 14 million new cases and 8 million cancer-related deaths in 2012 1. In both sexes

33

combined, the five most common cancers worldwide were the lung (13.0% of the total), breast (11.9%),

34

colorectum (9.7%), prostate (7.9%), and stomach (6.8%) cancers; they constitute half of the overall global

35

cancer burden 1. In the United States, there would be approximately 843,820 new cases of cancer diagnosed in

36

women and 841,390 in men; meanwhile expected 595,690 cancer deaths (314,290 men, 281,400 women) in

37

2017 as estimated by the American Cancer Society 2.

38 39

Diet is a bidirectional risk factor that actively affects cancer development. Several dietary factors, such as

40

non-excessive calories, increased intake of whole grains, fruits and vegetables, dietary fibers, reduced intake of

41

red meat, and less sugar consumption reduced risk of developing cancers 3-7. A wide array of population-based

42

studies has highlighted plant-based diet in cancer prevention

43

significant sources of beneficial bioactive compounds. NCI (national cancer institute) promotes the

44

‘Five-A-Day for Better Health’ program to encourage people in the United States to eat at least five servings a

45

day of fruits and vegetables, to reduce the risk of cancer and other chronic diseases. Epidemiological studies

46

suggest that, high intake of fruit and vegetables (especially cruciferous vegetables) have a moderately reduced

47

risk of cancer at several sites, especially for oral cavity and the upper gastrointestinal tract cancers 10-12. Whole

48

grains, abundant in dietary phytochemicals and fibers, are associated with reduced risk of gastrointestinal and

49

pancreatic cancers

5, 8-9

. Vegetables, fruits and whole grains are all

13-15

. The association between plant-based diet and reduced risk of other common cancers,

3


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50

such as breast cancer, prostate cancer, liver cancer and bladder cancer are not conclusive 7, 11-12, 14, 16. Summarily,

51

it is recommended to increase intake of vegetables, whole fruits and whole grains with a wide variety for cancer

52

and other chronic disease prevention, especially for those people who have original low consumption 9, 15, 17.

53 5-6

54

Dietary approach helps provide preventive, safe and economical anti-cancer strategies

. The increase in the

55

cost of health care and drug prices and potential side effects promotes researches on alternative modes of

56

anti-cancer approaches 18. According to World Cancer Research Fund (WCRF), approximately one third of the

57

most common cancers could be prevented through changes in lifestyle, such as diet, body weight management

58

and physical activity19. The potential protective dietary components against cancer generally include

59

phytochemicals, selenium, folic acid, vitamin B-12, vitamin D, chlorophyll, antioxidants (including

60

carotenoids), dietary fibers, and prebiotics; while red meats and excessive calorie intake increase risk of cancer

61

3-4, 6, 16, 19-20

62

consumption of whole grains, fruits and vegetables for prevention of chronic disease including cancer

63

21-22

64

effects and low toxicity of dietary agents 7, 18, 23. Encouraging in-vitro studies have associated some non-toxic or

65

low-toxic cocktails of food components (such as phytochemicals) with anti-cancer activities and even

66

synergistic effects in human cancer cells

67

compounds may related to regulation on more than one signal transduction pathway, stabilization of the

68

compounds, or increasing the bioavailability of compounds 18, 25.

. Dietary guidelines, with the support of epidemiological evidence, recommend increased 5, 17, 19,

. Advantages of anti-cancer strategies by dietary approach could be achieved from additive and synergistic

24-28

. The mechanism behind the synergism effects of bioactive

69 70

Anti-cancer benefits of plant-based foods are related to the actions of phytochemicals. Phytochemicals are

71

chemical compounds that occur naturally in plants after secondary metabolism, where phyto refers to "plant" in 4



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Greek. Based on chemical structure, phytochemicals can be generally classified into carotenoids, polyphenols,

73

nitrogen-containing compounds and organosulfur compounds

74

lignans, coumarins and stilbenes, etc.) and alkaloids (e.g. pyrrolidine derivatives, tropane derivatives,

75

pyrrolizidine derivatives, and piperidine derivatives, etc.) are the two largest groups of phytochemicals in plants

76

with bioactivities, while polyphenols have broad distribution in fruits, vegetables, whole grains, herbs and

77

spices, alkaloids have more typical distribution in medicine herbs

78

intake through food, additive and synergistic effects of dietary phytochemicals are consistently observed in

79

many studies 9.

23, 29

. Phenolics (e.g. flavonoids, phenolic acids,

30-33

. As special benefits of phytochemicals

80 81

Phytochemicals not only act as antioxidants affecting DNA (deoxyribonucleic acid), integrity, most of them

82

participate in anti-cancer signaling cascades that are related to cell survival, proliferation and invasion, at

83

transcriptional and post-transcriptional levels.

84

process that governs cells activities, include cell cycle arrest, proliferation, apoptosis, autophagy, and migration.

85

The molecular targets in cell signaling transduction pathways for phytochemicals include membrane receptors,

86

kinases, downstream cancerous or tumor-suppressor proteins, transcriptional factors, miRNAs (small

87

interfering ribonucleic acid), cyclins and caspases

88

protein, STAT3 (signal transducer and activator of transcription 3)) are central players in anti-cancer actions,

89

while some markers and downstream proteins are more specifically linked to certain cell behaviors: for

90

example, cyclins are related to cell cycle regulation and proliferation, caspases are related to apoptosis and

91

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is more related to inflammation 39-40.

5, 26, 34-35

. Cell signaling is the communication and interaction

36-38

. Some molecular targets (e.g. p53 tumor suppressor

92 93

The objective of this review is to discuss the recent publications that investigated anti-cancer activities of 5


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94

phytochemicals through targeting a wide variety of cell signaling pathways, at transcriptional or

95

post-transcriptional levels.

96 97

Dietary phytochemicals and their plant sources

98

Dietary phytochemicals are majorly derived from plant foods, such as fruits, vegetables and whole grains

99

(Table 1). There are thousands of phytochemicals have been found to be naturally produced in plants, their

100

function is highly related to chemical structure and functional groups. Phytochemicals have great chemical

101

diversity, majorly include phenolics, alkaloids, carotenoids, nitrogen-containing compounds and organosulfur

102

compounds

103

distribution in fruits, vegetables, whole grains, spices and herbs, either in their free or bound forms

104

They are a class of chemical compounds consisting of a hydroxyl group bonded directly to an aromatic

105

hydrocarbon group and can be categorized to subgroups by their backbone, including flavonoids, phenolic acids,

106

lignans, coumarins, chromones, antraquinones, and stilbenes

107

anthoxathins (flavones and flavonols), flavanones, flavanonols, flavans (flavanols, thearubigin and

108

proanthocyanidins), anthocyanins, and isoflavonoids

109

containing sulfur. They typically have foul odor and can be widely found in spices, fruit, nuts, vegetables and

110

fungi, especially garlics, green onions and cruciferous vegetables

111

phytochemicals containing at least one nitrogen atom that traditionally isolated from herbal medicine plants32, 47.

112

They usually have a bitter taste with various pharmacological activities including anti-inflammation,

113

anti-bacterial, psychotropic and stimulant activities29, 32, 47.

9, 23

. Phenolic compounds, naturally produced by plants and microorganisms, have a wide

23, 44

.

29, 43-45

. Flavonoids are further classified to

. Organosulfur compounds are organic compounds

3, 20, 46

114 115

23, 33, 41-43

Carcinogenesis and cell signaling transduction 6


. Alkaloids are another big class of


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116

Cancer formation (i.e. carcinogenesis) is a multistep process whereby normal cells are reprogrammed to

117

undergo uncontrolled cell division and transformed into cancer cells, as latterly form a malignant mass (tumor)

118

48-50

119

cancer theory recognizes the carcinogenesis process as briefly three steps: tumor initiation, promotion and

120

progression

121

example the initial uptake of carcinogenic agent and its distribution to organs and tissues where metabolic

122

activation or detoxification can occur, and the covalent interactions between reactive species and targeted DNA,

123

resulted in genotoxic damage and cell transformation

124

relatively lengthy and reversible evolution process that allows preneoplastic cells to accumulate through

125

expanded survival and proliferation. The promotion process is typically regulated by cell signaling transduction

126

pathways with participators of receptors, kinases, regulatory proteins, transcriptional factors and cyclins

127

Progression, the final stage of neoplastic transformation, is marked by cell behaviors of fast-speed growth and

128

high invasive and metastatic potential 51, 53. After progression, the cancer cells invade and migrate to secondary

129

sites through lymph system (metastasis)

130

microenvironment is critical for cancer development and metastasis and is a promising therapeutic target for

131

reduced risk of resistance and tumor recurrence 40.

. Changes at cellular, genetic and epigenetic levels would all contribute to this progression. The classic

50-52

. Initiation is the rapid and trigger process that involves the exposure to a carcinogen, for

5, 51, 53

. Different from initiation, tumor promotion is a

39, 54

.

55-56

. The bidirectional communication between cells and their

132 133

One typical mechanism of action of anti-cancer phytochemicals is that they regulate adaptive cellular stress

134

response pathways. The whole picture of the molecule cross-talk for cancer cell fate is still not totally clear.

135

However, despite in such conditions that some molecules directly work on nuclei DNA, cellular regulation is

136

carried out by signal transduction, which normally begins with interactions between extracellular substances

137

and cell membrane receptors, followed by cascades consist of regulatory proteins and/or transcription factors, 7


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thus affects expression of oncogenes and defensive proteins, resulting in different cell fates (e.g. apoptosis,

139

cell-cycle arrest, proliferation, or invasion)and reflective feedbacks to upstream5, 36-37, 54, 57-58. Most evidence

140

supports that phytochemicals intervene the signaling pathways and finally regulate on downstream

141

genes/proteins related with specific cell behavior: for instance, Bax, Bcl-2 family proteins and caspases are

142

related with apoptosis, Myc is related with cell cycle arrest, cyclins and CDK (cyclin-dependent kinases) are

143

related with cell proliferation, and MMPs (matrix metalloproteinase) are related with invasion

144

participators along signaling pathways can be regulated either via activation (phosphorylation and cleavage) or

145

expression (at genetic, epigenetic or translational levels) 5, 51, 53.

54, 56, 59-60

. The

146 147

Mechanism of action: molecular targets of signal transduction pathways

148 149

Effects of dietary phytochemicals on cancer initiation

150

Initiation of a cancer requires exposure to carcinogen, DNA damage and activation of oncogene

151

Carcinogens are typically transformed by phase I metabolizing enzymes to more DNA-binding reactive forms,

152

but those metabolites can be detoxified through conjugation catalyzed by phase Ⅱ metabolizing enzymes into

153

water-soluble forms which can then be eliminated from the body; where both enzymes can be targets for drug

154

intervention

155

promotion

156

stress and antioxidant profile, phase I and phase II enzyme action are highly related to cancer initiation.

157

Antioxidant phytochemicals are typically capable of capturing free radicals, hence influence antioxidant

158

response, DNA damage/repair, and tumor promotion

159

bio-activation or detoxification of carcinogens through affecting phaseⅠand phaseⅡenzyme activities,

51, 53

.

61-62

. Early research related singlet oxygen and other free radicals with DNA damage and tumor

51, 61

. Several mechanisms, especially those associated with DNA damage and repair, e.g. oxidative

63-65

. Phytochemicals showed their impact on

8



160

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including affecting cytochrome P450 and antioxidant enzymes 66-68.

161 162

Phase I metabolism reactions, such as hydrolysis, oxidation, reduction and deamination, play vital roles in

163

metabolic activation for carcinogens and some bioactive compounds. Various studies have indicated that the

164

superfamily of enzymes, as specific cytochrome P450 form (CYP450), activate a wide range of known

165

carcinogens via phase I metabolism. 69-70. On the other hand, CYP450- catalyzed oxidative metabolism of drugs

166

and bioactive phytochemicals could be considered as detoxification process

167

hemoproteins, are the terminal oxidase enzymes in electron transfer chains, while the term P450 was derived

168

from the spectrophotometric peak at the maximum absorption wavelength of 450 nm when discovered 71. Genes

169

encoding CYP enzymes are named following standard nomenclature with group serial number, subfamily code

170

and gene serial number (For example, human CYP1A1 gene encodes cytochrome P450 1A1 enzyme).

171

Phytochemicals have shown impacts on CYP450 through a host of CYP genes. Dietary flavonoids has been

172

found to modulate the CYP450 system through induction, activation and inhibition of specific CYP isozymes 72.

173

Earlier researches have showed that many flavonoids, flavone, naringenin, tangeretin and tea flavonoids,

174

inhibited 450 2B-, 2E1- and 3A-dependent activities, while flavone, naringenin, tangeretin also inhibited

175

CYP1A2 dependent metabolism

176

variant CYP2A6.25 conferred new substrate specificity toward 7-ethoxycoumarin, coumarin, flavone,

177

α-naphthoflavone, flavanone and hydroxyflavanone, while CYP2A6 affects flavonoid hydroxylation

178

metabolism and CYP2A6 mutations may suppress anti-cancer activities of flavonoids and result in tumor

179

growth 75.

71-72

. CYP450, a subfamily of

73-74

. Recent point mutation research of CYP2A6 showed that a polymorphic

180 181

The phase Ⅱ enzyme induction system crucially acts in cellular stress response to eliminate a broad range of 9


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182

electrophilic and oxidative toxicants before they damage the DNA 61-62, 76. Antioxidant phytochemicals protect

183

cell components not only by scavenging free radicals, but also by inducing de novo expression of genes that

184

encode defensive proteins, e.g. phase Ⅱ enzymes and/or antioxidant enzymes. Those enzymes catalyze

185

conjugation and neutralize electrophilic chemicals by sulfation, glucuronidation, glutathioylation, acetylation,

186

methylation, etc., the representatives include glutathione peroxidase (GPx), glutamate cysteine ligase (GCL),

187

gamma-glutamylcysteine

188

diphosphate-glucuronosyl transferases), superoxide dismutase (SOD), NAD(P)H quinone oxidoreductase (NQO)

189

and heme oxygenase-1 (HO-1) 61-62

synthetase

(γ-GCS),

glutathione

S-transferase

(GST),

UGT

(uridine

190 191

There are two underlying mechanisms for phase Ⅱ enzyme induction: Nrf2–ARE (nuclear factor erythroid

192

2-related factor-antioxidant-responsive element) signaling and AhR–XRE (aryl hydrocarbon receptor–

193

xenobiotic-responsive element) signaling 77-79. The 5’-flanking regions of certain stress-response genes contain

194

a common antioxidant-responsive cis-element, known as the ARE, which is bound and regulated by leucine

195

zipper (bZIP) transcription factors, such as Nrf, Jun, Fra, Fos, Maf and Ah receptor 78, 80. Nrf2 is a basic helix–

196

loop–helix transcription factor that involves in antagonizing cancer initiation, it regulates the expression of a

197

host phase Ⅱ enzymes, hence assists carcinogens detoxification and oxidative stress prevention

198

cytoplasmic actin-bound inhibitor of Nrf2, the Kelch-like-ECH-associated protein 1 (KEAP1), blocks its

199

translocation to the nucleus; oxidants can oxidize and phase Ⅱ enzyme can covalently modify the cysteine

200

residues of KEAP1 and dislocate Nrf2

201

3-kinase), ERKs (extracellular signal–regulated kinases), JNKs (c-Jun N-terminal kinases) and protein kinase C

202

(PKC), phosphorylate Nrf2 at serine (S) and/or threonine (T) residues, hence help release Nrf2 from KEAP1

203

and subsequently translocate to the nucleus, triggering protective antioxidant responses

77

. A

76, 81

. Certain kinases, e.g. PI3K(phosphatidylinositol-4,5-bisphosphate

10


80, 82-83

. Earlier


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204

researches showed several phytochemicals induced activation of phaseⅡdetoxifying enzymes in vitro via

205

Nrf2-ARE regulation (Table 2), which are related to adaptive pathways (e.g. mitogen-activated protein kinase

206

pathways)

207

Nrf2/Keap1 pathway activation, with increased levels of enzymatic antioxidants and decreased levels of

208

inflammatory promotors

209

downregulation of Fen1 expression, where Fen1 (Flap endonuclease 1) is a DNA repair-specific nuclease and

210

its overexpression is related to breast cancer development

211

expression in prostate cancer cells through DNA demethylation and histone modifications in epigenetic

212

regulations

213

epigenetically restored Nrf2 gene expression in prostate cancer cells through demethylation the Nrf2 promoter

214

CpGs, and hence upregulated gene expression of Nrf2 downstream detoxification enzymes HO-1 and NQO-1

215

91

84-87

. A recent study reports dietary cocoa was protective against colitis-associated cancer through

88

. Curcumin inhibited proliferation of breast cancer cells through Nrf2-mediated

89

. Sulforaphane was suggested to enhance Nrf2

90

. Z-Ligustilide, a phytochemical from widely used herb Radix Angelicae Sinensis in Asia,

.

216 217

However, even traditionally Nrf2 has been considered as a tumor suppressor due to anti-oxidant and

218

cytoprotective activities, recent studies indicate that hyperactivation of the Nrf2 favors the survival of

219

malignant cells, which make Nrf2 play dual roles in cancer

220

frequently upregulated in different types of tumors, which correlate with tumor aggressiveness and resistance to

221

therapy, the cellular defense response of Nrf2/HO-1 is also a promising target for overcoming resistance to

222

cancer therapies 92

79

. On the other hand, since Nrf2 and HO-1 are

223 224

Effects of dietary phytochemicals on cancer promotion signaling: regulation of cell proliferation,

225

apoptosis, cell cycle, and autophagy 11


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226

Once oncogenes get activated and carcinogenesis gets initiated, cells start self-defense actions which can be

227

promoted by certain phytochemicals

228

among extracellular matrix, cell membrane, plasma and nucleus via multiple regulators. After signal

229

transduction, cells give reflective responses and take actions on deciding cell fate, such as cell proliferation,

230

apoptosis, and cell cycle arrest

231

regulators, such as Bax, Bad, Bcl-2 family proteins and caspases; cell cycle regulators, such as myc and Chks

232

(Checkpoint kinase); and proliferation regulators, such as cyclins, Cdcs (cell-division cycle proteins) and CDKs

233

(cyclin-dependent kinases)

234

phytochemicals on cellular signaling transduction are listed in Table 3.

5-6, 27, 93

. Carcinogenesis signal transduction is an interactive process

27, 50, 57

. The final targets of cell signaling pathways majorly include: apoptosis

53-54, 56, 59-60

. The major signaling pathways is shown in Figure 1 and the effects of

235 236

MAPK pathways

237

MAPK/ ERK pathway (MAPK for mitogen-activated protein kinase, ERK for extracellular signal-regulated

238

kinase) is an essential route in cell survival and growth regulation, which can be targeted by phytochemical for

239

pro-apoptosis, anti-invasion and anti-proliferation effects in various cancers

240

downstream effectors of membrane receptors, e.g. ER (estrogen receptor), EGFR (epidermal growth factor

241

receptor) and TNFα (tumor necrosis factor alpha)

242

(mitogen-activated protein kinase kinase)-ERK transduction cascade, where Ras is an activator and

243

Raf-MEK-ERK is a crucial link that comprised of three protein kinases: a MAPK kinase kinase (MAPKKK, for

244

instance Raf), a MAPK kinase (MAPKK, for instance MEK) and a MAPK, typical terminal MAPKs include

245

ERKs, JNKs (c-Jun amino-terminal kinases, also known as SAPKs), and p38 kinases 57, 95. JNKs, for instance,

246

are reported to phosphorylate Bcl-2 and BH3-only proteins thus to encourage apoptosis

247

pathways activated by stress, MAPK pathway can both function as tumor suppressor or pro-oncogenic signal in

58, 94-95

. It is one of the main

58, 96

. This route can also be described as Ras-Raf-MEK

12


96-97

. As adaptive


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248

different malignant transformation situations, understanding the divergent nature of MAPK signaling activation

249

is critical in investigating chemopreventive effects of phytochemicals 57, 94. Ursolic acid was reported to trigger

250

caspase-dependent apoptosis in human osteosarcoma cells via the activation of ERK1/2 MAPK pathway, while

251

UA-induced apoptosis was significantly abolished under ERK1/2 inhibitor treatment

252

flavonoid, induced MAPK-dependent apoptosis and ER (endoplasmic reticulum) stress in human non-small cell

253

lung cancer cells through upregulation of ERK, JNK and p38 MAPK. The contribution of MAPK signaling was

254

confirmed by transfection tests with specific MAPK siRNAs 99. Many other phytochemicals, e.g. resveratrol, ,

255

kampferol, gingerol, genistein, sulforaphane, and isothiocyanates, have exhibited anti-cancer effects (especially

256

pro-apoptosis) in various cancer cells through MAPK pathways28, 94, 100-105(Table 3).

98

. Fisetin, a dietary

257 258

Akt signaling pathways

259

Another primary signaling channel, the PI3K/Akt (PI3K for phosphoinositide 3-kinase, Akt for protein kinase B)

260

pathway, was also prevailingly targeted in anti-cancer research

261

receives extracellular signals from multiple membrane receptors (e.g. EGFR), and ubiquitously participated in

262

regulation of cell survival as well as angiogenesis 108-109. The PI3K pathway largely contributes to the glycolytic

263

phenotype of cancer cells via the serine/threonine kinase Akt, while this glycolytic phenotype is observed in

264

major cancers

265

activation of PI3K: RTK activation results in PI(3,4,5)P3 and PI(3,4)P2 production by PI3Ks (a lipid kinase

266

family) at the inner side of the plasma membrane, while Akt interacts with these phospholipids by inducing its

267

translocation to the inner membrane after phosphorylation and activation by PDK (phosphoinositide-dependent

268

kinase) 1 and 2 112-113. Akt is highly sensitive to levels of EGF (epidermal growth factor) and regulates a series

269

of transcription factors, e.g. NF-κB, further activation of Akt phosphorylation leads to the promotion of cell

106-107

. This prototypic survival pathway also

110-111

. Its signaling mechanisms include engagement of receptor tyrosine kinases (RTKs) and

13


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270

proliferation and resistance to apoptosis, while downstream effectors e.g. Bcl-2, caspases, GSK3β (glycogen

271

synthase kinase 3-beta), endothelial NOS (nitric oxide synthase), and mTOR (mammalian target of rapamycin)

272

107-108, 114

273

inhibit Akt/PI3K signaling and result in anti-cancer activities toward anti-proliferation, pro-apoptosis and

274

anti-invasion

275

apoptosis in breast cancer cells via suppression of PI3K/Akt at Ser473 and activation of FOXO3a (forkhead box

276

O3), which subsequently increased the expression levels of cyclin-dependent kinase inhibitor p27 and p21 and

277

decreased expression levels of cyclin B and cyclin D

278

different breast cancer cells via ErbB2/ER-PI3K-Akt-mTOR-S6K1 signaling pathway. The cells in response to

279

sulforaphane were differ in the expression pattern of growth factors or estrogen receptors and PTEN

280

(phosphatase and tensin homolog deleted on chromosome ten) suppressor, suggesting both ErbB2 and ER serve

281

as upstream receptors for sulforaphane-induced PI3K/Akt inhibition

282

biflavonoid, reduced tumorigenesis by suppressing activation of PI3K/Akt/FoxO pathways in transgenic

283

adenocarcinoma of the mouse prostate (TRAMP) mice, while inhibition of Akt (Ser473) and FoxO3a (Ser253)

284

phosphorylation resulted in decreased binding and increased nuclear retention of FoxO3a 123.

. A wide array of phytochemicals, such as luteolin, resveratrol, and curcumin, have been reported to

115-120

(Table 3). Flavone, apigenin and luteolin were reported to induce cell cycle arrest and

121

. Sulforaphane inhibited growth of phenotypically

122

. Apigenin, a widely distributed plant

285 286

Wnt/β-catenin signaling pathways

287

Wnt/β-catenin signaling is another frequent signaling abnormalities that has been discovered in major human

288

cancers, including liver, lung, gastric, ovarian, breast, colon, leukemia, endometrial, brain, melanoma and

289

thyroid

290

epithelial-mesenchymal interactions

291

Frizzled family transmembrane receptors and results in β-catenin accumulation in the nucleus, thus interacts

38, 124

. This pathway is highly involved in process of cell survival, proliferation, migration, and 38, 125-126

. Its activation requires the binding of Wnt-protein ligand to

14



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292

with transcriptional factors and activates target genes like s c-myc, cyclin D, c-jun, Met, Snail and VEGF

293

(vascular endothelial growth factor)38,

294

curcumin and EGCG (epigallocatechin-3-gallate) 124, 128-129 (Table 3). In most cases, glycogen synthase kinase 3

295

(GSK-3) negatively regulates β-catenin stability via phosphorylation and degradation of the transcription

296

coactivator β-catenin, while GSK-3 can further be regulated by upstream kinases from Akt and MAPK

297

pathways130. 3,5,4-trimethoxystilbene (a natural analog of resveratrol), antagonized breast cancer invasion via

298

Wnt signaling and upstream Akt/GSK-3β regulation, accompanied with reduced the expression and nuclear

299

translocation of β-catenin

300

by promoting GSK-3β-independent β-catenin phosphorylation/degradation in colon cancer cells and suppressed

301

β-catenin dependent genes cyclin D1 and myc 129.

127

.Wnt/β-catenin pathway are regulated by phytochemicals such as

128

. However, EGCG, the major green tea phenol, inhibited Wnt/β-catenin signaling

302 303

JAK/STAT signaling pathways

304

JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway, in response to growth

305

factors and cytokines, is a signaling cascade regulates gene expression related to various cellular functions

306

including proliferation, growth and migration131-132. JAK, associated with cytoplasmic domains of membrane

307

receptor subunits, is activated after ligand binding-induced multimerization of receptor subunits

308

Activated JAKs subsequently phosphorylate STATs, then STATs translocate to nucleus and transcriptionally

309

regulates on a wide array of genes, including: apoptosis/survival-related Bcl-2, p53 and survivin, growth-related

310

PCNA (proliferating cell nuclear antigen), cyclin D and myc, and premetastatic MMP, IL-6 (interleukin-6) and

311

CXCL3 (chemokine ligand 3, or C-X-C motif ligand 3)

312

isothiocyanates from cruciferous vegetables) reversed the survival and growth advantage mediated by

313

oncogenic STAT5 and triggered cell death, the study identified STAT5 and to a lesser extent STAT1/STAT2 as

133-134

.

131, 135-136

15


. Sulforaphane and moringin (an

Page 17 of 48


93

314

novel targets of moringin

. Carnosic acid induced apoptosis via JAK2/STAT3 signaling pathway in human

315

colon cancer cells: it inhibited DNA binding and the reporter gene activity of STAT3, attenuated the expression

316

of STAT3 target gene products (such as survivin and cyclin Ds), and activated apoptosis cascade via induction

317

of p53 and Bax, downregulation of Bcl-2 family, and initiation of caspase cascade 137.

318 319

The tumor suppressor p53

320

The tumor suppressor protein p53 is central to defensive actions against carcinogenesis138-141. As the guardian

321

of the genome, p53 protein binds to DNA and facilitates multiple anti-cancer progresses especially via

322

activating apoptosis cascade and can be targeted by various phytochemicals

323

activated in response to stress signals, loss of p53 function (either via mutation or disturbed upstream signaling)

324

is a common feature in major human cancers

325

p53 signaling via increasing both expression and phosphorylation in MDA-MB-231 breast cancer cells, the

326

activation was reported to be calcium-dependent

327

not observed, the authors suggested p53 expression upregulation was likely due to alterations in protein stability

328

and proteasomal processing rate 143. Quercetin enhanced apoptosis induced by 5-fluorouracil (anti-cancer drug)

329

in colorectal cancer cells through p53 modulation, the dependence of p53 was confirmed by small interference

330

RNA (siRNA) in and p53 knockout cells 144. The p53 protein signaling has crosslinks with major pathways, e.g

331

Akt and MAPK. Akt activation induced phosphorylation in MDM2 (mouse double minute 2 homolog) protein

332

(a key p53 function regulator) was reported to inactivate p53 141, whereas p53 attenuated Akt signaling through

333

modulating membrane phospholipid composition

334

oleanolic acid, were linked to downregulated Akt, upregulated p53, and increased cell cycle rest and apoptotic

335

cancer cell death

142

. The p53 signaling pathway is

138, 142

. Quercetin, resveratrol, EGCG and piceatannol activated

143

. In the same study, increase in mRNA encoding p53 was

139

. Various dietary phytochemicals such as curcumin, and

27, 145-146

. The p53 protein also functionally interacts with MAPK pathways, MAP kinases

16



Page 18 of 48

336

phosphorylate and activate p53 under stress stimuli, while p53 actively serves as an upstream regulator for

337

MAPK signaling via transcriptional activation of dual specificity phosphatases

338

induced cell cycle arrest and apoptosis associated with the stimulation of p-p53, p53, and MAPKs in colon

339

cancer cells: the critical role of p53 was confirmed when ECG-induced apoptosis was blocked by p53 inhibitor

340

with restored cell viability and impaired caspase-3 and pro-apoptotic protein activity.; JNK and p38 (upon

341

activation by p53) were identified as necessary for ECG-induced apoptosis in the same study 147.

140

.. ECG (epicatechin gallate)

342 343

Energy regulation and Autophagy pathways

344

Autophagy is the adaptive response and survival mechanism in cells, where cell shut down and undergo

345

degradation of unnecessary cellular processes or dysfunctional cell components through lysosome action

346

Even tumor cells adapt well to poor nutrient and hypoxic conditions, energetic failure via blocking glucose

347

uptake from mitochondrial respiratory chain triggers autophagy

348

rely on energy state, intervention through ATP (adenosine triphosphate) synthesis or mitochondrial oxidative

349

phosphorylation chain serves as potential pathways for stimulating cancer cell death

350

metabolic stress induces autophagy through mTOR signaling, the role of autophagy in that case is divergent

351

from its role in serving as survival mechanism in normal cells

352

and promoters are related to chemoprevention mechanisms: many cancer drugs and ionizing radiation increases

353

autophagy, autophagy limits genome damage and cancer progression; on the other hand, inhibiting autophagy

354

under nutrition-deprived condition promotes apoptotic cancer cell death

355

autophagy (by Atg5 or Atg7 knockout, Atg for autophagy protein) inhibited tumor growth in the cells with wild

356

type p53 expression, but encouraged tumor growth in Ras mutant, p53 null cells

357

regulated by phytochemicals such as ursolic acid and sulforaphane122, 154 (Table 3). Delicaflavone induced

148

.

149-150

. Since cell division and growth highly

150

. In cancer cells,

149, 151

. Paradoxically, both autophagy inhibitors

17


149, 151-152

. Genetic inhibition of

153

. Autophagy could be

Page 19 of 48


358

autophagic cell death via increasing the ratio of LC3-II to LC3-I (LC3 for microtubule-associated protein 1

359

light chain 3), the generation of acidic vesicular organelles, and autolysosomes formation in the human lung

360

cancer cells; the upstream regulation of these effects was related to downregulation of Akt/mTOR/p70S6K

361

signaling pathway

362

involvement of oxidative stress production: curcumin enhanced conversion of LC3-I, degradation of

363

sequestome-1, and formation of puncta (an autophagosome marker); curcumin-induced cell death was blocked

364

by autophagosome lysosome fusion inhibitor and an strong antioxidant; however, reactive oxygen species (ROS)

365

production-dependent activation of ERK and p38 MAPK were not involved in curcumin-induced autophagy 156..

366

Interestingly, 2’,3’-dimethoxyflavanone, a flavonoid family member, increased conversion of autophagy marker

367

LC3 and ubiquitination of caspase-8 in breast cancer cells, however blocking autophagy degradation did not

368

show any change in the degree of LC3 conversion, LC3 lipidation inhibition test suggested this flavonoid

369

induced apoptosis via LC3 conversion-mediated activation of caspase-8 157.

155

. Curcumin markedly induced autophagic cell death in colon cancer cells with

370 371

Effects of dietary phytochemicals on tumor progression: regulation of inflammation, invasion,

372

angiogenesis and metastasis

373 374

Anti-inflammation

375

Inflammation, a protective response under harmful stimuli involving immune cells, blood vessels, and

376

molecular mediators in normal tissues, is yet recognized as a risk factor in certain cancers due to carcinogenic

377

actions of inflammatory cells: stimulating DNA damage and transformation, releasing survival and growth

378

factors, encouraging angiogenesis and lymphangiogenesis, antagonizing host defense, and facilitating invasion

379

via protease overexpression, ECM (extracellular matrix) remodeling and cancer cell coating for disseminating 18



Page 20 of 48

158-159

380

cells via lymphatics and capillaries

. Growth factors and cytokines also both work as messengers for

381

downstream inflammatory signaling. Some growth factors, for instance, EGF and transforming growth factor

382

(TGF) participate in regulation of cell proliferation and invasion during inflammation, in both tissue repair

383

process for a normal tissue and tumor cell growth process for a tumor

384

factors (TNF) are two major messenger cytokines, their interaction or independent activities activate regulatory

385

proteins or transcription factors in downstream inflammation pathways, e.g. JAK/STAT or NF-κB signaling

386

pathway 162-163. These pro-inflammatory cytokines (such as TNF-α, IL-1β, and IL-6) also work as mediators for

387

NO, hence are also involved in angiogenesis signaling

388

resveratrol, inhibited inflammation in physiological responses and cancer development28,

389

Resveratrol suppressed IL-6-induced ICAM-1 (Intercellular adhesion molecule 1, namely CD54) expression via

390

attenuating STAT3 phosphorylation and hence interfering with Rac-mediated pathways, the study suggested

391

resveratrol benefits endothelial responses to cytokines during inflammation

392

receptor 9 (TLR-9) agonist-induced inflammation in prostate cancer cells, while proliferative inflammatory

393

atrophy was frequently linked to prostate cancer development. The protective effects of EGCG against

394

inflammation in the prostate cancer were reported to be independent of the androgen receptor and p53 status 167.

160-161

. Interleukins and tumor necrosis

164-165

. Many phytochemicals, such as kaempferol and 166

(Table 3)..

166

. EGCG suppressed in Toll-like

395 396

NF-κB transcription factor

397

NF-κB is a transcription factor which regulates certain genes associated with cell proliferation, inflammation,

398

invasion and angiogenesis, and plays key role in cancer progression and metastasis168-171. NF-κB is typically

399

overexpressed in cancer cells. It is activated by many proinflammatory stimuli such as TNF-α, EGF, and IL-1β,

400

and it regulates a wide array of cancer-related genes, including invasive and metastatic genes MMP, ICAM-1,

401

ELAM-1 (endothelial-leukocyte adhesion molecule 1), and VCAM-1 (vascular cell adhesion molecule 1); 19


Page 21 of 48


402

angiogenetic gene VEGF; energy metabolism gene GLUT3; and survival genes Bcl-2, TRAP, p53 and Fas

403

211-213. NF-κB dimers are sequestered in the cytoplasm by biding a family of its inhibitors, called IκBs

404

(Inhibitor of κB), and can be activated by IκB degradation via upstream kinase IKK (IκB kinase) under

405

stimuli168,

406

triterpene that can be found in rice bran, wheat germ and olives, inhibited inflammatory actions in DSS-induced

407

acute colitis mouse model; squalene downregulated COX-2 (cyclooxygenase), inducible nitric oxide synthase,

408

and cytokines via suppressing p38 MAPK and NF-κB signaling pathways, whereas STAT3 and FOXP3

409

(forkhead box p3) were not involved174. Plumbagin, a naphthoquinone constituent of plants, suppressed the

410

invasion of HER2-overexpressing breast cancer cells via repressing activation of NF-κB: plumbagin reduced

411

NF-κB phosphorylation and transcriptional activity along with downstream MMP-9 expression, silencing of

412

NF-κB p65 increased sensitivity of breast cancer cells to anti-invasion effects of plumbagin175. NF-κB

413

inhibition by plumbagin was associated with IKK inhibition, knockdown of IKKα increased sensitivity of

414

breast cancer cells to plumbagin-induced decrease of NF-κB transcriptional activity and MMP-9 expression175.

171-173

. NF-κB is regulated by various phytochemicals (Table 3). Squalene, a hydrocarbon and

415 416

Anti-invasion

417

Cancer invasion is a cell- and tissue-driven process which involves tissue remodeling and allow cancer cells to

418

invade adjacent tissues and then migrate distant sites, it is a prerequisite for metastasis

419

cancer cells must breakdown their surrounding ECM and get access to circulation system, and MMPs are the

420

major enzymes taking this duty

421

exhibited significant anti-invasion activities179-182 (Table 3). kaempferol inhibited migration, adhesion and

422

invasion as well as downregulated activity and expression of MMP-2 and MMP-9 in human breast cancer cells,

423

the upstream signaling was linked to PKC/MAPK/AP-1 (activator protein 1) cascade

176-177

. During spread,

176, 178

. Phytochemicals such as curcumin, resveratrol and sulforaphane

20


180

.. Curcumin,


Page 22 of 48

424

demethoxycurcumin and bisdemethoxycurcumin differentially (bisdemethoxycurcumin > demethoxycurcumin >

425

curcumin) inhibited human fibrosarcoma cancer cell invasion through the downregulation of MMPs and uPA

426

(urokinase plasminogen activator), while cell migration was not affected 179. Curcumin suppressed proliferation

427

and invasion in non-small cell lung cancer cells through regulating MTA1 (metastasis-associated protein 1)

428

-mediated Wnt/β-catenin pathway, while MTA1

429

and have been detected in a wide variety of aggressive tumors

430

invasion in non-small cell lung cancer cells via IL-6/JAK/STAT3 pathway, the key role of STAT3 in invasion

431

was confirmed when knockdown of STAT3 by siRNA showed anti-invasion effects, invasive proteins such as

432

MMP-2, MMP-7 and ICAM-1 were also downregulated 184.

overexpression is important to cell invasion and metastasis 183

. Curcumin also suppressed proliferation and

433 434

Anti-angiogenesis

435

Tumor growth and metastasis actively adopts the process of new blood vessel formation (termed as

436

angiogenesis), which requires both oxygen and nutrients, hence in the case of malignant tumors, hypoxia and

437

nutrient limitation stimulate expression of pro-angiogenic factors to recruit de novo and existing vasculature

438

throughout the tumor

439

tumorigenesis. Several specific genes are labeled as switch to adjust the balance between proangiogenic and

440

antiangiogenic molecules from cancer cells themselves or the host microenvironment, e.g. the gene coding

441

VEGF

442

binding to receptor, both VEGF release and expression can be regulated by phytochemicals 187-188. Kaempferol

443

inhibited angiogenesis and tumor growth in chicken embryo induced by ovarian cancer cells, along with

444

downregulation of VEGF expression at both mRNA and protein levels

445

downregulation of kaempferol on VEGF was realized via both HIF1-dependent (Akt/HIF) and

185

. Excessive angiogenesis feeds diseased tissue and impairs normal tissue in

186-187

. VEGF is a principal messenger to initiate cellular angiogenesis signal transduction upon its

21


189

. The same study also indicated

Page 23 of 48


446

HIF1-independent (ESRRA) pathways 189. Curcumin inhibited tumor growth and angiogenesis in an orthotopic

447

mouse model of human pancreatic cancer；correspondingly it suppressed activation of transcriptional factor

448

NF-κB in cell and tumor samples, and further downregulated NF-κB-dependent gene products (VEGF, cyclin

449

D1, MMP-9, COX-2, IKKα, and IKKβ) in tumor tissues 190.

450 451

Anti-metastasis

452

As one of the hallmarks of malignant tumor, metastasis describes the immigration process within which cancer

453

cells travel to other parts of body through blood or lymph vessels from their tissue that they original developed

454

191

455

anoikis, angiogenesis, transport through vessels and outgrowth of secondary tumors

456

tumor growth and liver metastasis of colorectal cancer in mouse model, in vitro tests associated anti-invasion

457

and EMT suppression effects with downregulation of Sp-1, FAK (focal adhesion kinase), and CD24 as well as

458

upregulation of E-cadherin expression

459

distal organs (including lung and liver) in transgenic adenocarcinoma of mouse prostate (TRAMP) model, and

460

suppressed expression levels of CXCR4 (chemokine receptor type 4) －a cytokine receptor important for

461

distant organ metastasis－in the prostate tissues 194. 4,4 -dihydroxy-trans-stilbene (DHS), a resveratrol analogue,

462

suppressed lung cancer invasion and metastasis in two in vivo models (mouse and zebrafish): DHS significantly

463

inhibited tumor growth, angiogenesis and liver-metastasis in mice lung cancer invasion model; DHS suppressed

464

cell dissemination, invasion and metastasis in zebrafish lung cancer invasion model; in vitro tests associated

465

DHS with reduced cell migration, invasion and cell cycle arrest at G1 phase via PCNA and PARP 1 (Poly

466

[ADP-ribose] polymerase 1) regulation

467

breast cancer in a xenograft mouse model with smaller tumors, less ulceration, and significantly less metastasis

. Metastasis is carried out via serial processes, such as epithelial-mesenchymal transition (EMT), invasion, 177, 192

. Curcumin inhibited

193

. Ursolic acid treatment inhibited metastasis of prostate cancer to

195

. Whole blueberry powder, enriched in diet, inhibited metastasis of

22



Page 24 of 48

468

to the inguinal lymph nodes; whole blueberry powder dietary treatment also upregulated serum levels of

469

anti-inflammatory cytokines including IP-10, IL-12, IL-10, and IL-2, and downregulated pro-inflammatory

470

cytokines IL-17, IL-4 and VEGF; however, several pro-inflammatory cytokines including TNF-α, IL-5, IL-6,

471

IL-1β, MCP-1, and FGF were also upregulated in serum samples of blue berry powder-enriched groups; while

472

in tumor samples, anti-inflammatory IP-10 and IL-12 were upregulated; these results shed lights on

473

anti-inflammation and anti-metastasis effects of blue berry powder via cytokine driven pathways. 196.

474 475

Effects of dietary phytochemicals on oncogenic and tumor suppressor miRNAs

476

MicroRNAs (miRNAs) are short non-coding RNA molecules (20-22 nucleotide), they negatively regulate gene

477

expression via silencing RNA

478

behaviors including cell cycle arrest, proliferation, apoptosis and invasion can be affected by miRNAs via

479

regulation on expression of oncogenic genes (e.g. Myc, Ras) and tumor suppressor genes p53

480

measuring miRNA expression in tissue samples from 264 lung cancer cases suggested that, high quercetin-rich

481

food intake was linked to expression of tumor suppressor miRNA-let-7 family, while other

482

carcinogenesis-related miRNA families (miR-146, miR-26, and miR-17) also exhibited significant difference

483

between high and low quercetin consumption 200. Sulforaphane, quercetin and catechins treatments alone or in

484

combination suppressed pancreatic cancer cell viability and growth through induction of miR-let-7 expression

485

and inhibition of kras expression, as miR-let-7 was demonstrated to be a direct regulator of Ras oncogene, and

486

hence regulate downstream cell cycle or apoptosis-related proteins, including CDKs, Bcl-2 family and caspases

487

201

488

expression of miR-210, which is a participator in hypoxia pathway

489

upregulation on miR-210 was achieved via stabilization of HA-tagged HIF-1α ((hypoxia-inducible factor 1

197

. miRNAs play important role in cancer promotion and progression, cell

198-199

. A study

. EGCG suppressed lung cancer cell proliferation rate and anchorage-independent growth via upregulated 202

23


. The same study also reported EGCG’s

Page 25 of 48


490

α)-but not the P402A/P564A-mutated HIF-1α, suggesting EGCG targets the oxygen-dependent degradation

491

domain

492

miR-19/PTEN/AKT/p53 axis: curcumin antagonized Bisphenol A-induced MCF-7 oncogenic miR-19

493

overexpression and cancer cell proliferation; curcumin upregulated PTEN, a tumor suppressor gene and direct

494

effector of miR-19; cucurmin downregulated downstream p-AKT, p-MDM2, p53, and PCNA 203.

of

202

HIF-1α

.

Curcumin

suppressed

MCF-7

breast

cancer

cell

proliferation

via

495 496

Large bunch of oncogenic miRNAs that causally linked to tumorigenic processes and metastasis have been

497

identified, offering potential molecular targets to dietary phytochemicals

498

response, expression of some miRNAs (such as miR-155 and miR-21) are upregulated, they are also considered

499

as oncogenic miRNAs due to their overexpression in several types of tumors

500

miR-200 family and miR-146, show impacts on epithelial-mesenchymal transition via gene expression of

501

E-cadherin pathway proteins including ZEB, Twist, Snail, Slug and TGF-β, and cell invasion indicators such as

502

NF-κB and MMPs

503

magnolol and palmatine chloride induced miR-200c expression in breast cancer cells, while miR-200c is a

504

tumor suppressor miRNA via downregulating E-cadherin expression and antagonizing invasion 204. Resveratrol

505

has been shown to downregulate oncogenic miRNAs targeting genes encoding Dicer1, such as miR-155,

506

miR-21, miR-196a, miR-25, miR-17, and miR-92a-2 in colon cancer cells

507

abolished expression of tumor suppressor PDCD4 (programmed cell death protein 4) or PTEN and negative

508

regulators of TGF signaling via Dicer, suggesting resveratrol to have anti-cancer as well as anti-metastatic

509

effects

510

upregulation and miR-663 independent approaches, and upregulated TGF signaling suppressor SMAD7

511

(mothers

198-199, 204-205

. During inflammatory

206-207

. Some miRNAs, such the

205

. A recent screening on 139 nature products reported three compounds - enoxolone,

208

. Those oncogenic miRNAs

208

. Additional tests suggested resveratrol also suppressed TGFβ1 expression via both miR-663

against

decapentaplegic

homolog

7)

metastasis

208

24


.

Resveratrol

also

downregulated


Page 26 of 48

512

IL-6/STAT3/miR-21 pathway and hence induced prostate cancer associated transcript 29 (PCAT29) expression,

513

which promotes tumor suppressor function and suppresses prostate cancer metastasis

514

renal cancer cell invasion while downregulating TOPflash reporter activity (indicator for monitoring

515

Wnt/β-catenin signaling pathway) and miR-1260b expression

516

miR-1260b (typically overexpressed in renal cancer cells) promoted cancer cell proliferation and invasion via

517

abolishing gene expression of tumor suppressors and negative regulators of Wnt-signaling (e.g. sFRP1, Dkk2,

518

SMAD4), which can be counteracted by miR-1260 inhibitor, hence inhibition of miR-1260b and Wnt pathway

519

by genistein antagonized by tumor progression and metastasis 210.

209

. Genistein inhibited

210

. The same study also reported oncogenic

520 521

Discussion and further prospects

522

The growing field of food and nutrition science increasingly offers new approaches to cancer chemoprevention

523

via targeting cellular signaling pathways. Currently data suggest: 1) increased intake of vegetables, fruits and

524

whole grains promisingly but not conclusively reduced risk of cancer development; 2) certain phytochemicals

525

hold great potential for cancer prevention while exhibiting anti-proliferation, pro-apoptosis, anti-invasion,

526

anti-inflammation, anti-metastasis effects; 3) phyochemicals are highly involved in cellular anti-cancer cross

527

talk at protein level, genetic level and epigenetic level. However, there lies challenges. Specificity and causality

528

behind those interactions between phytochemicals and cell signaling transduction targets requires further

529

mapping, and the metabolism factors requires further investigation.

530 531

Signaling pathways regulate biological processes in all cells. Currently, certain small-molecule inhibitors and

532

monoclonal antibodies are categorized as targeted therapies for cancer, because these agents act via disturbing

533

specific signaling pathways in malignant cells1. However, for phytochemicals acquired from diet, most of them 25


Page 27 of 48


5, 18, 211

534

target on multiple signaling nodes, hence their application in cancer therapy are controversial

. From

535

preventive side, current dietary guidelines suggest increasing consumption of whole grains and a variety of

536

fruits and vegetables other than single component for cancer and chronic disease prevention17, 19. There are

537

some existing clinical data support the efficacy of several phytochemicals, such as curcumin, resveratrol,

538

lycopene, folates and tea polyphenols, for cancer chemoprevention in high-risk populations6, 212-213. However,

539

since correlation between diet and biomarkers of cancer can only be accurately determined by studying large

540

populations over prolonged periods of time, it is generally recommended to increase consumption of whole

541

foods, and reduce intake of red meat and sugar in cancer prevention diet other than taking dietary supplements

542

or relying on a single compound

543

dietary factors in clinical trials, it is useful to understand how dietary compounds regulate signal transduction

544

pathways against cancer, how they interact with immune system and anti-oxidant system, and hence to help

545

understand anti-cancer mechanisms of action and to help provide effective, safe and affordable solutions in

546

cancer prevention or therapy for human beings 6, 9, 16, 18.

4, 6, 19

. Although limitation still exists and it is difficult to characterize the

547 548

The difficulty lies in identifying the effective and safe doses of phytochemicals among humans. It is not clear

549

how could these anti-cancer effects of phytochemicals present in physiological concentrations and for the

550

metabolites8, 214. In the clinical testing of anti-cancer drugs, the safety and proof of efficacy of drugs are

551

assessed through several phases, however, around 70% of the anti-cancer drugs did not make favorable effect

552

on the malignancy in phase II clinical trials even extensive preclinical data showing their efficacy in cells and

553

animal models215. For phytochemicals, it is even more difficult to converse the doses in models into humans,

554

due to cofounding factors in food matrix, the metabolism issues and the synergistic effects4, 6, 8, 216. Except for

555

investigating the promising anticancer effects of phytochemicals in cancer cells, it is necessary to identify the 26



Page 28 of 48

556

physiological effective concentration and the effective dosage that could be acquired from food after

557

metabolism. There was considerable discrepancy between pharmacological and dietary-related dose of

558

phytochemicals (10- to 100- fold), while the length of intervention also cofounded the extrapolation of the

559

potential value of effective dose from dietary intake217-219. It is also suggested that the dose in the animal study

560

should not be simply conversed to a human equivalent dose by body weight, new models adopting factors

561

including oxygen utilization, caloric expenditure, basal metabolism, blood volume, circulating plasma proteins,

562

and renal function have been invented220. Dose translation of phytochemicals between models and from animal

563

to human study still needs further study, and the effective doses should be investigated in the food matrix and

564

should consider metabolic processes.

565 566

Another possible challenge for chemoprevention by phytochemicals is that their bioavailabilities were reported

567

to be low42, 216, 221-222. Some phytochemicals, such as phenolics with rhamnose structure, could not be absorbed

568

through the small intestine and were degraded by the rhamnosidases produced by the colonic microflora42. Low

569

oral bioavailability for resveratrol was found due to extensive metabolism in the intestine and liver, which

570

would undermine in vivo effects221. Some other phytochemicals have better absorption. Acylated flavonoids

571

(e.g. EGCG) are absorbed without deconjugation and hydrolysis, and isoflavone aglycones could be absorbed

572

from the stomach42, 44. Certain methods, such as analogs, nanotechnology, and enhanced delivery systems were

573

developed to improve bioavailability216,

574

reported to have enhanced bioavailability221. Application of nanoparticles as carriers increased the aqueous

575

solubility, stability, bioavailability, and target specificity of several phytochemicals like EGCG, quercetin,

576

resveratrol and curcumin223. However, there is long way to go to identify the effective condition for

577

phytochemicals.

221, 223

. Resveratrol analogs, such as methylated derivatives was

27


Page 29 of 48


578 579

One thing could not be neglect for dietary intake of phytochemicals is that, diet is a comprehensive and

580

long-term health factor. Whole foods could be more effective for cancer prevention since benefits can be

581

acquired from synergistic effects of bioactive compounds and food components

582

and bioavailability of oral phytochemicals from foods, there is more work to be done such as identifying lowest

583

effective doses and evaluating application factors among in vitro experiments, in vivo studies and real-life

584

situation. The future study may dig into the combination of phytochemicals and multiple-channel targeted

585

approaches, as to lower active dose and to lower potential side effects 29.

7, 211

. Considering low content

586 587

Abbreviations

588

AhR, aryl hydrocarbon receptor; Akt, protein kinase B; ARE, antioxidant-responsive element; AMPK, 5'

589

AMP-activated protein kinase; Cdc, cell-division cycle proteins; CDK, cyclin-dependent kinases; Chemokines,

590

chemotactic cytokines; Chk, checkpoint kinase; CXCR4, chemokine receptor type 4; CYP450, cytochrome

591

P450; ECM, extracellular matrix; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor;

592

ELAM-1, endothelial-leukocyte adhesion molecule 1; ER, endoplasmic reticulum; ERK, extracellular

593

signal-regulated

594

gamma-glutamylcysteine synthetase; GLUT, glucose transporter; GPx, glutathione peroxidase; GSK-3,

595

glycogen synthase kinase 3; GRO-α, growth-related oncogene-α; GST, glutathione S-transferase; HIF-1,

596

hypoxia-inducible factor-1; HO-1, heme oxygenase-1; ICAM-1, Intercellular adhesion molecule 1; IFN-γ,

597

interferon gamma; IL, interleukin; IκB, inhibitor of Κb; IKK, IκB kinase; JAK, Janus kinase; IP-10, interferon

598

gamma (IFN-γ)-induced protein 10; JNKs, c-Jun amino-terminal kinases; KEAP1, Kelch-like-ECH-associated

599

protein 1; LC3, microtubule-associated protein 1 light chain 3; LPS, lipopolysaccharide; MAPK,

kinase;

Fen1,

Flap

endonuclease

1;

GCL,

28


glutamate

cysteine

ligase;

γ-GCS,


Page 30 of 48

600

mitogen-activated protein kinase; miRNA, microRNA; MDC, monocyte-derived chemokine; MMPs, matrix

601

metalloproteinase; mTOR, mammalian target of rapamycin; NCI, national cancer institute; NQO, NAD(P)H

602

quinone oxidoreductase; Nrf2, nuclear factor erythroid 2-related factor; PCNA, proliferating cell nuclear

603

antigen; PARP 1, Poly [ADP-ribose] polymerase 1; PI3K, phosphoinositide 3-kinase; RTK, receptor tyrosine

604

kinases; ROS, reactive oxygen species; SMAD, mothers against decapentaplegic homolog; SOD, superoxide

605

dismutase; STAT, signal transducer and activator of transcription; TGF, transforming growth factor; TLR9,

606

Toll-like receptor 9; TNFα, tumor necrosis factor alpha; TRAMP, transgenic adenocarcinoma of the mouse

607

prostate; UGT, uridine diphosphate-glucuronosyl transferases; uPA, urokinase plasminogen activator; VCAM-1,

608

vascular cell adhesion molecule 1; XRE, xenobiotic responsive element

609 610

Funding sources:

611

This work was supported by the China Scholarship Council.

612 613

References:

614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629

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1083 1084

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1085

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Figure.1 Major signaling pathways involved in cancer progression.

Chemical category Flavonoids

31, 33, 224-227

Phytochemicals

Plant sources

Anthoxathins (flavones and flavonols)

Widely distributed in fruits, vegetables, whole grains and herbs

Anthocyanins


Flavanols (catechin, gallocatechin, catechin

Tea products, cocas, fruits and vegetables

3-gallate, gallocatechin 3-gallate, epicatechins, epigallocatechin, epicatechin 3-gallate, and epigallocatechin 3-gallate) Isoflavonoids (e.g. genistein, daidzein, and

Legumes (such as soybean, peas) and legume-based products

pelargonidin) Stilbenes41, 228-229

Stilbenoids (e.g. resveratrol)

Grape plants, peanuts, blue berries, mulberries, blue berries and raspberries

Organosulfur

Allicin

Garlics, green onions

compounds20, 46, 201

Diallyl sulfide


sulforophane

Allium, broccoli, sprouts and cruciferous vegetables

S-allyl cysteine


capsaicin

Chili peppers

Piperine

Black peppers, long peppers

Indole-3-carbinol

Cruciferous vegetables

Diosgenin

Fenugreek

β-carotene

Carrots, pumpkins, sweet potatoes and a variety of fruits and

Alkaloids26, 30, 47

Carotenoids

213, 230

vegetables

222, 231-232

Triterpenoids

Diarylheptanoids

1086

87, 203

Lycopene

Tomatoes, carrots, watermelons, gac, papaya

Ursolic acid


curcumin

Turmeric plants

Table1 Select phytochemicals and plant sources

1087 1088 1089 1090

Table 2 Effects of phytochemicals on Nrf2 pathway and induction of phaseⅡenzymes Phytochemicals

Model

Dose

Duration

Effects on

Effects on phaseⅡenzymes

Nrf2 pathway Artemisitene

Human breast cancer cells

0.5 ~ 2.5 µM

16 h

Activation

Increase in HO-1 and NQO-1 expression233

Caffeic acid

Porcine renal epithelial cells

phenethyl ester

and rat kidney epithelial cells

5 ~ 30 µM

6h

Activation

41


Increase in HO-1 expression87

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Carnosol

Rat pheochromocytoma cells

10 µM

6h

Activation


Cocoa

Mice with colitis-associated

10% in diet

62 d

Activation

Increase in NQO-1 and UGT expression234

10 ~ 30 µM

6h

Activation


Breast cancer cells

20 ~ 30 µM

24 h

Activation

N/A89

Bovine aortic endothelial

50 µM

6h

Activation


0.2% in diet

30 d

N/A

cancer (colon tissues collected) Curcumin

Porcine renal epithelial cells and rat kidney epithelial cells

EGCG

cells Green tea

Female hairless mice

Increase in activities of GPx and NQO in

polyphenols

small bowl, liver and lung, increase in GST activity in small bowl and liver235

Punicalagin

Mouse macrophages

Sulforaphane

Rat (lymphocytes collected)

Z Ligustilide


50 ~ 200 µM

8h

Activation

25 mg/kg BW

Samples

Activation

(Intravenous)

collected at

NQO-1expression, no change in GSTM1,

0.5 ~ 24 h

SOD, UGT1A1, or UGT1A6 expression66

Mouse prostate cancer cells

2.5 µM

5d

Activation

Mouse prostate cancer cells

6.25 ~ 50 µM

3d

Activation

Increase in GPx1, GSTT1, HO-1 and

Increase in NQO-1 expression90 Increase in HO-1, NQO1, and UGT1A1 expression91

1091 1092

Table 3 Anti-cancer effects of phytochemicals via regulating cellular signaling pathways Phytochemicals

Model

Dose

Duration

Effects on

Anti-cancer effects

pathway Apigenin


28 ~ 98 µM

12 ~ 48 h

↓Akt

Anti-proliferation, pro-apoptosis121

10 ~ 20 µM

16 h

↓Akt

Anti-proliferation123

Transgenic adenocarcinoma

20 ~ 50 µg/d,

50 w

↓Akt

Anti-carcinoma differentiation,

of the mouse prostate

gavage

Human prostate cancer cells

anti-metastasis123

(TRAMP) mice Avenanthramide

Human cervical cancer

80 µM

12 h

↓Wnt/β-catenin


Pro-apoptosis137

cells Carnosic acid

Human colon cancer cells

50 ~ 100 µM

24 h

↓STAT3

Curcumin


25 ~ 50 µM

12 ~ 24 h

↓Akt

Anti-proliferation, anti-migration, pro-autophagy237


20 µM

20 h

↑MAPK

Pro-autophagy156


10 µM

24 h

↓NF-κB

Anti-proliferation, anti-invasion238

Human neuroblastoma cells

25 ~ 50 µM

48 h

↓NF-κB

Pro-apoptosis27

Human non-small cell lung

15 ~ 30 µM

48 h

↓Wnt/β-catenin

Anti-proliferation,

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anti-invasion183

cancer cells Human pancreatic cancer

50 µM

48 h

↓NF-κB


cells Human small cell lung

15 µM

24 ~72 h

↓STAT3

cancer cells

Anti-proliferation, anti-migration, anti-invasion, anti-angiogenesis184

Orthotopic mouse model

0.6% in diet

33 w

↓NF-κB

Anti-tumor growth, anti-angiogenesis190

with human pancreatic cancer Rat and human

30 ~ 50 µM

6h

↓Akt, ↓NF-κB

Delicaflavone

Human non-small cell lung

20 ~ 40 µg/mL

48 ~72 h

↓Akt, ↓mTOR

Human prostate cancer

100 ~ 500 µM

48 h

↓Akt, ↑MAPK


cells Dimethoxyflavanone

Anti-proliferation, pro-autophagy155

cancer cells Diallyl disulfide

Anti-proliferation, anti-migration117

glioblastomas cells


100 µM

48 h

↑MAPK


ECG


30 µM

8 ~ 24 h

↓Akt, ↑MAPK


EGCG


50 µM

0.5 ~ 8 h

↑MAPK



40 ~ 80 µM

15 h

↓Wnt/β-catenin



40 µg/mL

24 h

↓NF-κB

Anti-proliferation,

cells

anti-migration, anti-inflammation167

Eupatilin

Human endometrial cancer

100 µM

0.5 ~ 1h

↓Akt, ↑MAPK

pro-apoptosis146

cells Fisetin

human non-small cell lung

75 µg/mL

24 h

↑MAPK


cancer cells Flavone

Anti-proliferation,


44 ~ 136 µM

12 ~ 48 h

↓Akt


Garlic acid

Human gastric carcinoma

2 ~ 3.5 µM

48 h

↓Akt, ↓NF-κB

Anti-migration, anti-invasion114

25 ~ 50 µM

24 h

↑MAPK

Anti-invasion, pro-apoptosis105

cells Genistein

Human hepatocellular carcinoma cells

Gingerol


10 ~ 50 µM

24 h

↑MAPK

Pro-apoptosis104

Grape

Human pancreatic cancer

40 ~ 60 µg/mL

48 h

↓Akt

Anti-proliferation,

Proanthocyanidin

cells

pro-apoptosis119

Xenograft Nude mouse

0.5% in diet

11 w

↓Akt

model of human pancreatic cancer

43


Anti-tumor growth, pro-apoptosis119

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Indole-3 carbinol


60 ~ 100 µM

48 h

↓Akt, ↓NF-κB


Kaempferol

Chicken embryo model of

20 µM, once, by

human ovarian cancer

implantation

5d

↓Akt,

Anti-tumor growth, anti-angiogenesis189

with cancer cells Human breast cancer cells

20 ~ 40 µM

24 h

↓MAPK

Anti-invasion180

Human monocytic cells

100 nM

24 h

↓MAPK

Anti-inflammation28

Human ovarian cancer cells

5 ~ 20 µM

16 h

↓Akt

Anti-proliferation, anti-angiogenesis189

Human ovarian cancer cells

Luteolin


40 ~ 80 µM

28 ~ 121 µM

24 h

12 ~ 48 h

↓MAPK,

Anti-proliferation,

↓NF-κB

anti-angiogenesis240

↓Akt


Mouse leukemic monocyte

8 ~ 16 µM

4h

↓Akt, ↓NF-κB

Anti-inflammation241

2 µM

0.5 h

↓STAT5,

Anti-proliferation,

↓NF-κB

anti-inflammation93

↑MAPK

Anti-proliferation,

macrophage cell Moringin

Human cervical cancer cells

Oleanolic acid

Human hepatoma cells

40 µM

16 h

anti-inflammation145 Oridonin


20 ~ 80 µM

48 h

↑MAPK

pro-apoptosis242

cells Quercetin

Anti-proliferation,

Human adenoid cystic

25~100 µM

24 h

↓Akt, ↓NF-κB

Anti-invasion, pro-apoptosis118

1g/kg, p.o. daily

32 d

↓Akt, ↓NF-κB

Anti-turmor growth,

carcinoma cells Xenograft nude mouse

pro-apoptosis118

model of human adenoid cystic cancer Resveratrol

Bovine aortic endothelial

100 µM

4h

↓STAT3

Anti-inflammation166

50 µM

24 h

↓MAPK,

Anti-proliferation,

↓NF-κB

Anti-inflammation,

cells Human pancreatic cancer cells

anti-invasion, pro-apoptosis103 Mouse with

50 µM/animal,

DMBA-induced skin tumor

topically, thrice

28 w

↓Akt

Anti-tumorigenesis, pro-apoptosis116

a week Lung metastatic mouse

16 µg/mL,

model of melanoma cancer

once, by tail

20 d

↓NF-κB

Anti-tumor growth, anti-metastasis195

vein injection with cancer cells Rottlerin


0.5 ~ 2 µM

48 h

↓Akt, ↓mTOR

44


Pro-autophagy, pro-apoptosis243


Page 46 of 48

cells Shikonin


2.5 ~ 5 µM

24 ~ 48 h

↓Akt

Pro-autophagy244

10 ~ 40 µM

3h

↓Akt

Anti-proliferation,

cells Sulforaphane


pro-autophagy122 Human cervical cancer

10 µM

0.5 h

cells Human colorectal cancer

10 ~ 20 µM

24 h

↓STAT5,

Anti-proliferation,

↓NF-κB

anti-inflammation93

↑MAPK


cells Trimethoxystilbene

Ursolic acid


20 µM


20 µM

24 h

24 h

↓Akt,

Anti-proliferation,

↓Wnt/β-catenin

anti-migration, anti-invasion128

↓Akt, ↓MAPK

Anti-proliferation, pro-apoptosis, pro-autophagy154

Human cervical cancer

40 ~ 60 µM

48 h

↓MAPK


cells Human colon cancer cells

10 ~ 40 µM

48 h

↓MAPK


Human osteosarcoma cells

20 µg/mL

24 h

↑MAPK


Transgenic adenocarcinoma of the mouse prostate

1% in diet

12 w

↓CXCR4

Anti-tumor growth,

↓NF-κB

anti-metastasis

(TRAMP) mice

1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 45


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Figure 1. Major signaling pathways involved in promotion and progression of carcinogenesis.

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TOC graphic

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Potential Mechanisms of Action of Dietary Phytochemicals for Cancer

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