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http://dx.doi.org/10.5487/TR.2017.33.4.273

Cancer Chemopreventive Potential of Procyanidin  

Lee, Yongkyu (Department of Food Science & Nutrition, Dongseo University)
Publication Information
Toxicological Research / v.33, no.4, 2017 , pp. 273-282 More about this Journal
Abstract
Chemoprevention entails the use of synthetic agents or naturally occurring dietary phytochemicals to prevent cancer development and progression. One promising chemopreventive agent, procyanidin, is a naturally occurring polyphenol that exhibits beneficial health effects including anti-inflammatory, antiproliferative, and antitumor activities. Currently, many preclinical reports suggest procyanidin as a promising lead compound for cancer prevention and treatment. As a potential anticancer agent, procyanidin has been shown to inhibit the proliferation of various cancer cells in "in vitro and in vivo". Procyanidin has numerous targets, many of which are components of intracellular signaling pathways, including proinflammatory mediators, regulators of cell survival and apoptosis, and angiogenic and metastatic mediators, and modulates a set of upstream kinases, transcription factors, and their regulators. Although remarkable progress characterizing the molecular mechanisms and targets underlying the anticancer properties of procyanidin has been made in the past decade, the chemopreventive targets or biomarkers of procyanidin action have not been completely elucidated. This review focuses on the apoptosis and tumor inhibitory effects of procyanidin with respect to its bioavailability.
Keywords
Chemoprevention; Procyanidin; Signaling pathway; Apoptosis; Biomarker; Transcription;
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1 Matito, C., Mastorakou, F., Centelles, J.J., Torres, J.L. and Cascante, M. (2003) Antiproliferative effect of antioxidant polyphenols from grape in murine Hepa-1c1c7. Eur. J. Nutr., 42, 43-49.   DOI
2 Torres, J.L., Varela, B., Garcia, M.T., Carilla, J., Matito, C., Centelles, J.J., Cascante, M., Sort, X. and Bobet, R. (2002) Valorization of grape (Vitis vinifera) byproducts. Antioxidant and biological properties of polyphenolic fractions differing in procyanidin composition and flavonol content. J. Agric. Food Chem., 50, 7548-7555.   DOI
3 Avelar, M.M. and Gouvea, C.M. (2012) Procyanidin $B_2$ cytotoxicity to MCF-7 human breast adenocarcinoma cells. Indian J. Pharm. Sci., 74, 351-355.   DOI
4 Liu, J., Zhang, W.Y., Kong, Z.H. and Ding, D.G. (2016) Induction of cell cycle arrest and apoptosis by grape seed procyanidin extract in human bladder cancer BIU87 cells. Eur. Rev. Med. Pharmacol. Sci., 20, 3282-3291.
5 Engelbrecht, A.M., Mattheyse, M., Ellis, B., Loos, B., Thomas, M., Smith, R., Peters, S., Smith, C. and Myburgh, K. (2007) Proanthocyanidin from grape seeds inactivates the PI3-kinase/PKB pathway and induces apoptosis in a colon cancer cell line. Cancer Lett., 258, 144-153.   DOI
6 Kaur, M., Mandair, R., Agarwal, R. and Agarwal, C. (2008) Grape seed extract induces cell cycle arrest and apoptosis in human colon carcinoma cells. Nutr. Cancer, 60 Suppl 1, 2-11.   DOI
7 Kaur, M., Singh, R.P. and Gu, M. (2006) Grape seed extract inhibits in vitro and in vivo growth of human colorectal carcinoma cells. Clin. Cancer Res., 12, 6194-6202.   DOI
8 Owczarek, K., Hrabec, E., Fichna, J., Sosnowska, D., Koziolkiewicz, M., Szymanski, J. and Lewandowska, U. (2017) Flavanols from Japanese quince (Chaenomeles japonica) fruit suppress expression of cyclooxygenase-2, metalloproteinase-9, and nuclear factor-${\kappa}B$ in human colon cancer cells. Acta Biochim. Pol., 64, 567-576.   DOI
9 Pierini, R., Kroon, P.A., Guyot, S., Ivory, K., Johnson, I.T. and Belshaw, N.J. (2008) Procyanidin effects on oesophageal adenocarcinoma cells strongly depend on flavan-3-ol degree of polymerization. Mol. Nutr. Food Res., 52, 1399-1407.   DOI
10 Wallace, T.C. and Giusti, M.M. (2010) Evaluation of parameters that affect the 4-dimethylaminocinnamaldehyde assay for flavanols and proanthocyanidins. J. Food Sci., 75, C619-C625.   DOI
11 Shoji, T., Masumoto, S., Moriichi, N., Kobori, M., Kanda, T., Shinmoto, H. and Tsushida, T. (2005) Procyanidin trimers to pentamers fractionated from apple inhibit melanogenesis in B16 mouse melanoma cells. J. Agric. Food Chem., 53, 6105-6111.   DOI
12 Singh, A., Misra, V., Thimmulappa, R.K., Lee, H., Ames, S., Hoque, M.O., Herman, J.G., Baylin, S.B., Sidransk, D., Gabrielson, E., Brock, M.V. and Biswal, S. (2006) Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer, PLoS Med., 3, e420.   DOI
13 Chung, Y.C., Huang, C.C., Chen, C.H., Chiang, H.C., Chen, K.B., Chen, Y.J., Liu, C.L., Chuang, L.T., Liu, M. and Hsu, C.P. (2012) Grape-seed procyanidins inhibit the in vitro growth and invasion of pancreatic carcinoma cells. Pancreas, 41, 447-454.   DOI
14 Hsu, C.P., Lin, Y.H., Chou, C.C., Zhou, S.P., Hsu, Y.C., Liu, C.L., Ku, F.M. and Chung, Y.C. (2009) Mechanisms of grape seed procyanidin-induced apoptosis in colorectal carcinoma cells. Anticancer Res., 29, 283-289.
15 Dinicola, S., Cucina, A., Pasqualato, A., D'Anselmi, F., Proietti, S., Lisi, E., Pasqua, G., Antonacci, D. and Bizzarri, M. (2012) Antiproliferative and apoptotic effects triggered by Grape Seed Extract (GSE) versus epigallocatechin and procyanidins on colon cancer cell lines. Int. J. Mol. Sci., 13, 651-664.   DOI
16 Mao, J.T., Xue, B., Smoake, J., Lu, Q.Y., Park, H., Henning, S.M., Burns, W., Bernabei, A., Elashoff, D., Serio, K.J. and Massie, L. (2016) MicroRNA-19a/b mediates grape seed procyanidin extract-induced anti-neoplastic effects against lung cancer. J. Nutr. Biochem., 34, 118-125.   DOI
17 Ohnuma, T., Anzai, E., Suzuki, Y., Shimoda, M., Saito, S., Nishiyama, T., Ogura, K. and Hiratsuka, A. (2015) Selective antagonization of activated Nrf2 and inhibition of cancer cell proliferation by procyanidins from Cinnamomi Cortex extract. Arch. Biochem. Biophys., 585, 17-24.   DOI
18 Wang, R., An, J., Ji, F., Jiao, H., Sun, H. and Zhou, D. (2008) Hypermethylation of the Keap1 gene in human lung cancer cell lines and lung cancer tissues. Biochem. Biophys. Res. Commun., 373, 151-154.   DOI
19 Shibata, T. Ohta, T., Tong, K.I., Kokubu, A., Odogawa, R., Tsuta, K., Asamura, H., Yamamoto, M. and Hirohashi, S. (2008) Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc. Natl. Acad. Sci. U.S.A., 105, 13568-13573.   DOI
20 Tyagi, A., Raina, K., Shrestha, S.P., Miller, B., Thompson, J.A., Wempe, M.F., Agarwal, R. and Agarwal, C. (2014) Procyanidin B2 3,3''-di-O-gallate, a biologically active constituent of grape seed extract, induces apoptosis in human prostate cancer cells via targeting NF-${\kappa}B$, Stat3 and AP1 transcription factors. Nutr. Cancer, 66, 736-746.   DOI
21 Mackenzie, G.G., Adamo, A.M., Decker, N.P. and Oteiza, P.I. (2008) Dimeric procyanidin $B_2$ inhibits constitutively active NF-${\kappa}B$ in Hodgkin's lymphoma cells independently of the presence of $I{\kappa}B$ mutations. Biochem. Pharmacol., 75, 1461-1471.   DOI
22 Fu, M., Wang, C., Wang, J., Zhang, X., Sakamaki, T., Yeung, Y.G., Chang, C., Hopp, T., Fuqua, S.A., Jaffray, E., Hay, R.T., Palvimo, J.J., Janne, O.A. and Pestell, R.G. (2002) Androgen receptor acetylation governs trans activation and MEKK1-induced apoptosis without affecting in vitro sumoylation and trans-repression function. Mol. Cell. Biol., 22, 3373-3388.   DOI
23 Shiota, M., Yokomizo, A., Masubuchi, D., Tada, Y., Inokuchi, J, Eto, M., Uchiumi, T., Fujimoto, N. and Naito, S. (2010) Tip60 promotes prostate cancer cell proliferation by translocation of androgen receptor into the nucleus. Prostate, 70, 540-554.
24 La, V.D., Bergeron, C., Gafner, S. and Grenier, D. (2009) Grape seed extract suppresses lipopolysaccharide-induced matrix metalloproteinase (MMP) secretion by macrophages and inhibits human MMP-1 and -9 activities. J. Periodontol., 80, 1875-1882.   DOI
25 Agarwal, C., Singh, R.P., Dhanalakshmi, S. and Agarwal, R. (2004) Anti-angiogenic efficacy of grape seed extract in endothelial cells. Oncol. Rep., 11, 681-685.
26 Malumbres, M. and Barbacid, M. (2001) To cycle or not to cycle: a critical decision in cancer. Nat. Rev. Cancer, 1, 222-231.   DOI
27 Taparia, S.S. and Khanna, A. (2016) Effect of procyanidinrich extract from natural cocoa powder on cellular viability, cell cycle progression, and chemoresistance in human epithelial ovarian carcinoma cell lines. Pharmacogn. Mag., 12, S109-S115.
28 Meeran, S.M. and Katiyar, S.K. (2007) Grape seed proanthocyanidins promote apoptosis in human epidermoid carcinoma A431 cells through alterations in Cdki-Cdk-cyclin cascade, and caspase-3 activation via loss of mitochondrial membrane potential. Exp. Dermatol., 16, 405-415.   DOI
29 Pierini, R., Kroon, P.A., Guyot, S., Johnson, I.T. and Belshaw, N.J. (2008) The procyanidin-mediated induction of apoptosis and cell-cycle arrest in esophageal adenocarcinoma cells is not dependent on p21 (Cip1/WAF1). Cancer Lett., 270, 234-241.   DOI
30 Sherr, C.J. (2000) Cell cycle control and cancer. Harvey Lect., 96, 73-92.
31 Taparia, S.S. and Khanna, A. (2016) Procyanidin-rich extract of natural cocoa powder causes ROS-mediated caspase-3 dependent apoptosis and reduction of pro-MMP-2 in epithelial ovarian carcinoma cell lines. Biomed. Pharmacother., 83, 130-140.   DOI
32 Connor, C.A., Adriaens, M., Pierini, R., Johnson, I.T. and Belshaw, N.J. (2014) Procyanidin induces apoptosis of esophageal adenocarcinoma cells via JNK activation of c-Jun. Nutr. Cancer, 66, 335-341.   DOI
33 Schroeter, H. (2004) Flavonoids, neuroprotective agent? Modulation of oxidative stress-induced MAP kinase signaling transduction in Flavonoids in Health and Disease (Packer, L. and Rice-Evans, C.A. Eds.). Marcel Dekker, New York, pp. 233-272.
34 Feng, L.L., Liu, B.X., Zhong, J.Y., Sun, L.B. and Yu, H.S. (2014) Effect of grape procyanidins on tumor angiogenesis in liver cancer xenograft models. Asian Pac. J. Cancer Prev., 15, 737-741.   DOI
35 Zhang, P., Singh, A., Yegnasubramanian, S., Esopi, D., Kombairaju, P., Bodas, M., Wu, H., Bova, S.G. and Biswal, S. (2010) Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth. Mol. Cancer Ther., 9, 336-346.   DOI
36 Kang, K.A. and Hyun, J.W. (2017) Oxidative stress, Nrf2, and epigenetic modification contribute to anticancer drug resistance. Toxicol. Res., 33, 1-5.   DOI
37 Dinicola, S., Pasqualato, A., Cucina, A., Coluccia, P., Ferranti, F., Canipari, R., Catizone, A., Proietti, S., D'Anselmi, F., Ricci, G., Palombo, A. and Bizzarri, M. (2014) Grape seed extract suppresses MDA-MB231 breast cancer cell migration and invasion. Eur. J. Nutr., 53, 421-431.   DOI
38 Wu, D.C., Li, S., Yang, D.Q. and Cui, Y.Y. (2011) Effects of Pinus massoniana bark extract on the adhesion and migration capabilities of HeLa cells. Fitoterapia, 82, 1202-1205.   DOI
39 Kang, N.J., Lee, K.W., Lee, D.E., Rogozin, E.A., Bode, A.M., Lee., H.J. and Dong, Z. (2008) Cocoa procyanidins suppress transformation by inhibiting mitogen-activated protein kinase kinase. J. Biol. Chem., 283, 20664-20673.   DOI
40 Januchowski, R., Wojtowicz, K., Sujka-Kordowska, P., Andrzejewska, M. and Zabel, M. (2013) MDR gene expression analysis of six drug-resistant ovarian cancer cell lines. Biomed. Res. Int., 2013, 241763.
41 He, L., Zhao, C., Yan, M., Zhang, L.Y. and Xia, Y.Z. (2009) Inhibition of P-glycoprotein function by procyanidine on blood-brain barrier. Phytother. Res., 23, 933-937.   DOI
42 Holt, R.R., Lazarus, S.A., Sullards, M.C., Zhu, Q.Y., Schramm, D.D. Hammerstone, J.F., Fraga, C.G., Schmitz, H.H. and Keen, C.L. (2002) Procyanidin dimer $B_2$ [epicatechin-(4beta-8)-epicatechin] in human plasma after the consumption of a flavanol-rich cocoa. Am. J. Clin. Nutr., 76, 798-804.   DOI
43 Spencer, J.P., Abd-el-Mohsen, M.M. and Rice-Evans, C. (2004) Cellular uptake and metabolism of flavonoids and their metabolites: implications for their bioactivity. Arch. Biochem. Biophys., 423, 148-161.   DOI
44 Stoupi, S., Williamson, G., Viton, F., Barron, D., King, L.J., Brown, J.E. and Clifford, M.N. (2010) In vivo bioavailability, absorption, excretion, and pharmacokinetics of [14C]procyanidin B2 in male rats. Drug Metab. Dispos., 38, 287-291.   DOI
45 Zhang, L., Wang, Y., Li, D., Ho, C.T., Li, J. and Wan, X. (2016) The absorption, distribution, metabolism and excretion of procyanidins. Food Funct., 7, 1273-1281.   DOI
46 Vigna, G.B., Costantini, F., Aldini, G., Carini, M., Catapano, A., Schena, F., Tangerini, A., Zanca, R., Bombardelli, E., Morazzoni, P., Mezzetti, A., Fellin, R. and Maffei Facino, R. (2003) Effect of a standardized grape seed extract on low-density lipoprotein susceptibility to oxidation in heavy smokers. Metabolism, 52, 1250-1257.   DOI
47 Chatelain, K., Phippen, S., McCabe, J., Teeters, C.A., O'Malley, S. and Kingsley, K. (2011) Cranberry and grape seed extracts inhibit the proliferative phenotype of oral squamous cell carcinomas. Evid. Based Complement. Alternat. Med., 2011, 467691.
48 Fu, M., Rao, M., Wang, C., Sakamaki, T., Wang, J., Di Vizio, D., Zhang, X., Albanese, C., Balk, S., Chang, C., Fan, S., Rosen, E., Palvimo, J.J., Janne, O.A., Muratoglu, S., Avantaggiati, M.L. and Pestell, R.G. (2003) Acetylation of androgen receptor enhances coactivator binding and promotes prostate cancer cell growth. Mol. Cell. Biol., 23, 8563-8575.   DOI
49 Agarwal, C., Sharma, Y., Zhao, J. and Agarwal, R. (2000) A polyphenolic fraction from grape seeds causes irreversible growth inhibition of breast carcinoma MDA-MB468 cells by inhibiting mitogen-activated protein kinases activation and inducing $G_1$ arrest and differentiation. Clin. Cancer Res., 6, 2921-2930.
50 Ye, X., Krohn, R.L., Liu, W., Joshi, S.S., Kuszynski, C.A., McGinn, T.R., Bagchi, M., Preuss, H.G., Stohs, S.J. and Bagchi, D. (1999) The cytotoxic effects of a novel IH636 grape seed proanthocyanidin extract on cultured human cancer cells. Mol. Cell. Biochem., 196, 99-108.   DOI
51 Tyagi, A., Agarwal, R. and Agarwal, C. (2003) Grape seed extract inhibits EGF-induced and constitutively active mitogenic signaling but activates JNK in human prostate carcinoma DU145 cells: possible role in antiproliferation and apoptosis. Oncogene, 22, 1302-1316.   DOI
52 Agarwal, C., Singh, R.P. and Agarwal, R. (2002) Grape seed extract induces apoptotic death of human prostate carcinoma DU145 cells via caspases activation accompanied by dissipation of mitochondrial membrane potential and cytochrome c release. Carcinogenesis, 23, 1869-1876.   DOI
53 Singh, R.P., Tyagi, A.K., Dhanalakshmi, S., Agarwal, R. and Agarwal, C. (2004) Grape seed extract inhibits advanced human prostate tumor growth and angiogenesis and upregulates insulin-like growth factor binding protein-3. Int. J. Cancer, 108, 733-740.   DOI
54 Engelbrecht, A.M., Mattheyse, M., Ellis, B., Loos, B., Thomas, M., Smith, R., Peters, S., Smith, C. and Myburgh, K. (2007) Proanthocyanidin from grape seeds inactivates the PI3-kinase/PKB pathway and induces apoptosis in a colon cancer cell line. Cancer Lett., 258, 144-153.   DOI
55 Gorlach, S., Wagner, W., Podsędek, A., Szewczyk, K., Koziolkiewicz, M. and Dastych, J. (2011) Procyanidins from Japanese quince (Chaenomeles japonica) fruit induce apoptosis in human colon cancer Caco-2 cells in a degree of polymerization-dependent manner. Natur. Cancer, 63, 1348-1360.   DOI
56 Yamakoshi, J., Saito, M., Kataoka, S. and Kikuchi, M. (2002) Safety evaluation of proanthocyanidin-rich extract from grape seeds. Food Chem. Toxicol., 40, 599-607.   DOI
57 Mittal, A., Elmets, C.A. and Katiyar, S.K. (2003) Dietary feeding of proanthocyanidins from grape seeds prevents photocarcinogenesis in SKH-1 hairless mice: relationship to decreased fat and lipid peroxidation. Carcinogenesis, 24, 1379-1388.   DOI
58 Dai, J. and Mumper, R.J. (2010) Plant phenolics: extraction, analysis and their antioxidant and anticancer properties. Molecules, 15, 7313-7352.   DOI
59 Suzuki, T., Tanaka, R., Hamada, S., Nakagawa, H. and Miyata, N. (2010) Design, synthesis, inhibitory activity, and binding mode study of novel DNA methyltransferase 1 inhibitors. Bioorg. Med. Chem. Lett., 20, 1124-1127.   DOI
60 Choi, K.C., Park, S., Lim, B.J., Seong, A.R., Lee, Y.H., Shiota, M., Yokomizo, A., Naito, S., Na, Y. and Yoon, H.G. (2011) Procyanidin B3, an inhibitor of histone acetyltransferase, enhances the action of antagonist for prostate cancer cells via inhibition of p300-dependent acetylation of androgen receptor. Biochem. J., 433, 235-244.   DOI
61 Shilpi, A., Parbin, S., Sengupta, D., Kar, S., Deb, M., Rath, S.K., Pradhan, N., Rakshit, M. and Patra, S.K. (2015) Mechanisms of DNA methyltransferase-inhibitor interactions: Procyanidin B2 shows new promise for therapeutic intervention of cancer. Chem. Biol. Interact., 233, 122-138.   DOI
62 Mao, J.T., Smoake, J., Park, H.K., Lu, Q.Y. and Xue, B. (2016) Grape seed procyanidin extract mediates antineoplastic effects against lung cancer via modulations of prostacyclin and 15-HETE eicosanoid pathways. Cancer Prev. Res. (Phila), 9, 925-932.   DOI
63 Hussain, S.P. and Harris, C.C. (2007) Inflammation and cancer: an ancient link with novel potentials. Int. J. Cancer, 121, 2373-2380.   DOI
64 Meeran, S.M. and Katiyar, S.K. (2008) Proanthocyanidins inhibit mitogenic and survival-signaling in vitro and tumor growth in vivo. Front. Biosci., 13, 887-897.   DOI
65 Zhao, B.X., Sun, Y.B., Wang, S.Q., Duan, L., Huo, Q.L., Ren, F. and Li, G.F. (2013) Grape seed procyanidin reversal of pglycoprotein associated multi-drug resistance via down-regulation of NF-${\kappa}B$ and MAPK/ERK mediated YB-1 activity in A2780/T cells. PLoS ONE, 8, e71071.   DOI
66 Lin, Y.S., Chen, S.F., Liu, C.L. and Nieh, S.J. (2012) The chemoadjuvant potential of grape seed procyanidins on p53-related cell death in oral cancer cells. J. Oral Pathol. Med., 41, 322-331.   DOI
67 Kaur, M., Agarwal, R. and Agarwal, C. (2006) Grape seed extract induces anoikis and caspase-mediated apoptosis in human prostate carcinoma LNCaP cells: possible role of ataxia telangiectasia mutated-p53 activation. Mol. Cancer Ther., 5, 1265-1274.
68 Cedo, L., Castell-Auvi, A., Pallares, V., Macia, A., Blay, M., Ardevol, A., Motilva, M.J. and Pinent, M. (2014) Gallic acid is an active component for the anticarcinogenic action of grape seed procyanidins in pancreatic cancer cells. Nutr. Cancer, 66, 88-96.   DOI
69 Lewandowska, U., Szewczyk, K., Owczarek, K., Hrabec, Z., Podsędek, A., Sosnowska, D. and Hrabec, E. (2013) Procyanidins from evening primrose (Oenothera paradoxa) defatted seeds inhibit invasiveness of breast cancer cells and modulate the expression of selected genes involved in angiogenesis, metastasis, and apoptosis. Nutr. Cancer, 65, 1219-1231.   DOI
70 Callejas, N.A., Casado, M., Bosca, L. and Martin-Sanz, P. (1999) Requirement of nuclear factor ${\kappa}B$ for the constitutive expression of nitric oxide synthase-2 and cyclooxygenase-2 in rat trophoblasts. J. Cell Sci., 112, 3147-3155.
71 Carpenter, C.L. and Cantley, L.C. (1996) Phosphoinositide kinases. Curr. Opin. Cell Biol., 8, 153-158.   DOI
72 Romashkova, J.A. and Makarov, S.S. (1999) NF-${\kappa}B$ is a target of AKT in anti-apoptotic PDGF signalling. Nature, 401, 86-90.   DOI
73 Stambolic, V., Suzuki, A., de la Pompa, J.L., Brothers, G.M., Mirtsos, C., Sasaki, T., Ruland, J., Penninger, J.M., Siderovski, D.P. and Mak, T.W. (1998) Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell, 95, 29-39.   DOI
74 Gu, L., Dagvadorj, A., Lutz, J., Leiby, B., Bonuccelli, G., Lisanti, M.P., Addya, S., Fortina, P., Dasgupta, A., Hyslop, T., Bubendorf, L. and Nevalainen, M.T. (2010) Transcription factor Stat3 stimulates metastatic behavior of human prostate cancer cells in vivo, whereas Stat5b has a preferential role in the promotion of prostate cancer cell viability and tumor growth. Am. J. Pathol., 176, 1959-1972.   DOI
75 Martin-Cordero, C., Leon-Gonzalez, A.J., Calderon-Montano, J.M., Burgos-Moron, E. and Lopez-Lazaro, M. (2012) Pro-oxidant natural products as anticancer agents. Curr. Drug Targets, 13, 1006-1028.   DOI
76 Xu, B. and Chang, S.K. (2012) Comparative study on antiproliferation properties and cellular antioxidant activities of commonly consumed food legumes against nine human cancer cell lines. Food Chem., 134, 1287-1296.   DOI
77 Li, S., Xu, M., Niu, Q., Xu, S., Din, Y., Yan, Y., Guo, S. and Li, F. (2015) Efficacy of procyanidins against in vivo cellular oxidative damage: a systematic review and meta-analysis. PLoS ONE, 10, e0139455.   DOI
78 Ouyang, X., Jessen, W.J., Al-Ahmadie, H., Serio, A.M., Lin, Y., Shih, W.J., Reuter, V.E., Scardino, P.T., Shen, M.M., Aronow, B.J., Vickers, A.J., Gerald, W.L. and Abate-Shen, C. (2008) Activator protein-1 transcription factors are associated with progression and recurrence of prostate cancer. Cancer Res., 68, 2132-2144.   DOI
79 Raina, K., Agarwal, C. and Agarwal, R. (2013) Effect of silibinin in human colorectal cancer cells: targeting the activation of NF-${\kappa}B$ signaling. Mol. Carcinog., 52, 195-206.   DOI
80 Sun, M., Liu, C., Nadiminty, N., Lou, W., Zhu, Y., Yang, J., Evans, C.P., Zhou, Q. and Gao A.C. (2012) Inhibition of Stat3 activation by sanguinarine suppresses prostate cancer cell growth and invasion. Prostate, 72, 82-89.   DOI
81 Zhu, Q.Y., Zhang, A., Tsang, D., Huang, Y. and Chen, Z.-Y. (1997) Stability of green tea catechins. J. Agric. Food Chem., 45, 4624-4628.   DOI
82 Ohnuma, T., Matsumoto, T., Itoi, A., Kawana, A., Nishiyama, T., Ogura, K. and Hiratsuka, A. (2011) Enhanced sensitivity of A549 cells to the cytotoxic action of anticancer drugs via suppression of Nrf2 by procyanidins from Cinnamomi Cortex extract. Biochem. Biophys. Res. Commun., 413, 623-629.   DOI
83 Zhu, Q.Y., Holt, R.R., Lazarus, S.A., Ensunsa, J.L., Hammerstone, J.F., Schmitz, H.H. and Keen, C.L. (2002) Stability of the flavan-3-ols epicatechin and catechin and related dimeric procyanidins derived from cocoa. J. Agric. Food Chem., 50, 1700-1705.   DOI
84 Yoshino, K., Suzuki, M., Sasaki, K., Miyase, T. and Sano, M. (1999) Formation of antioxidants from (-)-epigallocatechin gallate in mild alkaline fluids, such as authentic intestinal juice and mouse plasma. J. Nutr. Biochem., 10, 223-229.   DOI
85 Serra, A., Macia, A., Romero, M.P., Valls, J., Blade, C., Arola, L. and Motilva, M.J. (2010) Bioavailability of procyanidin dimers and trimers and matrix food effects in in vitro and in vivo models. Br. J. Nutr., 103, 944-952.   DOI
86 Spencer, J.P., Chaudry, F., Pannala, A.S., Srai, S.K., Debnam, E. and Rice-Evans, C. (2000) Decomposition of cocoa procyanidins in the gastric milieu. Biochem. Biophys. Res. Commun., 272, 236-241.   DOI
87 Cooper, K.A., Donovan, J.L., Waterhouse, A.L. and Williamson, G. (2008) Cocoa and health: a decade of research. Br. J. Nutr., 99, 1-11.
88 Wang, K., Brems, J.J., Gamelli, R.L. and Holterman, A.X. (2010) Survivin signaling is regulated through nuclear factor-${\kappa}B$ pathway during glycochenodeoxycholate-induced hepatocyte apoptosis. Biochim. Biophys. Acta, 1803, 1368-1375.   DOI
89 Wu, X., Senechal, K., Neshat, M.S., Whang, Y.E. and Sawers, C.L. (1998) The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc. Natl. Acad. Sci. U.S.A., 95, 15587-15591.   DOI
90 Agarwal, C., Veluri, R., Kaur, M., Chou, S.C., Thompson, J.A. and Agarwal, R. (2007) Fractionation of high molecular weight tannins in grape seed extract and identification of procyanidin B2-3,3'-di-O-gallate as a major active constituent causing growth inhibition and apoptotic death of DU145 human prostate carcinoma cells. Carcinogenesis, 28, 1478-1484.   DOI
91 Katiyar, S.K. (2006) Matrix metalloproteinases in cancer metastasis: molecular targets for prostate cancer prevention by green tea polyphenols and grape seed proanthocyanidins. Endocr. Metab. Immune Disord. Drug Targets, 6, 17-24.   DOI
92 Glade, M.J. (1997) Food, nutrition, and the prevention of cancer, a global perspective. American institute for cancer research/World cancer research fund, American Institute for Cancer Research. Nutrition, 15, 523-526.
93 Doll, R. and Peto, R. (1981) The causes of cancer, quantitative estimates of risks of cancer in the United States today. J. Natl. Cancer Inst., 66, 1191-1308.
94 Riboli, E. and Norat, T. (2003) Epidemiologic evidence of the protective effect of fruit and vegetables on cancer risk. Am. J. Clin. Nutr., 78, 559S-569S.   DOI
95 Willet, W.C., Stampfer, M.J., Colditz, G.A., Rosner, B.A. and Speizer, F.E. (1990) Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N. Engl. J. Med., 323, 1664-1672.   DOI
96 Zhao, J., Wang, J., Chen, Y. and Agarwal, R. (1999) Antitumor-promoting activity of a polyphenolic fraction isolated from grape seeds in the mouse skin two-stage initiation-promotion protocol and identification of procyanidin $B_5$-3'-gallate as the most effective antioxidant constituent. Carcinogenesis, 20, 1737-1745.   DOI