Review 1635 Biological/Chemopreventive Activity of Stilbenes and their Effect on Colon Cancer Author Agnes M. Rimando1, Nanjoo Suh2, 3 Affiliation 1 United States Department of Agriculture, Agricultural Research Service, Natural Products Utilization Research Unit, University, MS, USA 2 Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA 3 The Cancer Institute of New Jersey, New Brunswick, NJ, USA Key words Abstract ventive agents. One of the best-characterized ●" resveratrol ! stilbenes, resveratrol, has been known as an anti- ●" stilbenes Colon cancer is one of the leading causes of can- oxidant and an anti-aging compound as well as ●" colon cancer cer death in men and women in Western coun- an anti-inflammatory agent. Stilbenes have di- ●" inflammation tries. Epidemiological studies have linked the verse pharmacological activities, which include consumption of fruits and vegetables to a re- cancer prevention, a cholesterol-lowering effect, duced risk of colon cancer, and small fruits are enhanced insulin sensitivity, and increased life- particularly rich sources of many active phyto- span. This review summarizes results related to chemical stilbenes, such as resveratrol and pter- the potential use of various stilbenes as cancer ostilbene. Recent advances in the prevention of chemopreventive agents, their mechanisms of colon cancer have stimulated an interest in diet action, as well as their pharmacokinetics and ef- and lifestyle as an effective means of interven- ficacy for the prevention of colon cancer in ani- tion. As constituents of small fruits such as mals and humans. grapes, berries and their products, stilbenes are under intense investigation as cancer chemopre- received May 7, 2008 Introduction wood in response to fungal infection [5], [6]. Al- revised July 21, 2008 ! though known as plant defense compounds, accepted July 30, 2008 Predicted death from colon cancer is estimated to these phytochemicals have an enormous diversi- Bibliography be almost 50,000 in the U.S.A. in 2008, making ty of effects on biological and cellular processes DOI 10.1055/s-0028-1088301 colon cancer the second leading cause of death applicable to human health. The biological ef- Planta Med 2008; 74: 1635– among all cancer types for men and women in fects of a well-characterized stilbene, resveratrol, 1643 the U.S.A. (American Cancer Society Facts and include its role as an inducer of cell differentia- © Georg Thieme Verlag KG Fig. 2008). With increasing awareness of disease tion, a mediator of anti-inflammatory action and Stuttgart · New York prevention, not only for colon cancer, changes in its effects as an antioxidant and anti-aging agent Published online October 8, diet and lifestyle have received much attention as [3], [7], [8], [9], [10]. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 2008 ISSN 0032-0943 an effective means of intervention of disease de- The distribution of stilbenes in the plant king- velopment. Experts allude to diets rich in fruits dom is wide. Resveratrol, for example, is found Correspondence and vegetables as a key for keeping healthy. Cer- in small fruits such as grapes and Vaccinium ber- Prof. Nanjoo Suh tain groups of compounds, such as polyphenols, ries [10], [11], peanuts [12] and in Polygonum Department of Chemical have gained popularity as health beneficial con- species [13]. Stilbenes structurally related to re- Biology Ernest Mario School of stituents in edible plants. Over the past decade, sveratrol have been found in a variety of foods as Pharmacy there have been increasing applications for natu- well as in medicinal plants (●" Table 1). Similar to Rutgers, The State University of rally derived phytochemicals as anti-inflamma- resveratrol, these phytochemicals have a multi- New Jersey tory and cancer chemopreventive agents [1], [2], tude of biological activities. Some in vitro and in 164 Frelinghuysen Road [3], [4]. vivo activities related to cancer are provided in Piscataway Stilbenes or stilbenoids are a well-known class of ●" Table 1. NJ 08854 naturally occurring phytochemicals. Stilbenes The demonstrated pharmacological properties of USA Tel.: +1-732-445-3400 (x226) bear the core structure of 1,2-diphenylethylene naturally occurring stilbenes have inspired the Fax: +1-732-445-0687 (●" Table 1). These compounds are stress metabo- synthesis of analogues in efforts to improve ac- [email protected] lites, produced in the leaves as well as in sap- tivity. For example, tamoxifen, with the chemical Rimando AMet al. Biological/Chemopreventive Activity of… Planta Med 2008; 74: 1635– 1643 1636 Review Table 1 Naturally-occurring stilbenes■●" Name R1 R2 R4 R5 Plant Source Anti-cancer related activity Astringin OGluc OH OH OH Picea spp. [94] Inhibits DMBA-induced lesions in mouse mammary glands [95] Desoxy- OH OH H OCH3 Rheum spp. [96], [97] Inhibits human tumor cell lines, A-549, rhapontigenin SK-OV-3, SK-MEL-2, XF-498 and HCT15 [98]; Inhibits CYP 1A1 and 1B1 [58] Isorhapontigenin OH OH OCH3 OH Picea spp. [94] Estrogenic in breast cancer cells MCF-7 or T-47 D [99] Isorhapontin OGluc OH OCH3 OH Picea spp. [94] Estrogenic in breast cancer cells MCF-7 or T-47 D [99] Oxyresveratrol OH OH H OH Morus spp. [100] Cytotoxic in human lung and colon cancer cells [101] Piceatannol OH OH OH OH Picea spp. [94], Inhibits human leukemia cell line U937 (Astringenin) Rheum undulatum [97] [102] and human bladder cancer cells [103] Piceid (Polydatin) OGluc OH H OH Vitis vinifera [104] Pinostilbene OH OCH3 HOHPinus sibirica [105] Inhibits cytochromes P450 1A1, 1A2, 1B1, and 2E1 [57], [58] Pinostilbenoside OH OCH3 HOGlucPinus spp. [106] Pinosylvin OH OH H H Alnus crispa [107], Inhibits human lymphoblastoid cell lines Pinus resinosa [108] Molt and Raji [109] Pinosylvin OH OCH3 HHAlnus crispa [107], monomethylether Pinus resinosa [108] Pterostilbene OCH3 OCH3 HOHVitis vinifera [110], Inhibits azoxymethane-induced ACF [51]; Vaccinium spp . [11] Inhibits cytochromes P450 1A1, 1A2, 1B1, Pterocarpus spp. [111] and 2E1 [57], [58] ResveratrolOHOHHOHVitis vinifera [5], Arachis Numerous studies, Inhibits cytochromes hypogaea [12], P450 1A1, 1A2, 1B1, and 2E1 [57], [58] Polygonum spp. [13] Resveratrol OCH3 OCH3 HOCH3 Virola elongata [112] Anti-proliferative activity towards trimethylether DU-145, LNCaP, M-14 and KB cells lines [113]; Inhibits cytochromes P450 1A2, 2E1 [57] Resveratroloside OH OH H OGluc Rhei palmati [114] Rhaponticin OGlucOHOHOCH3 Rheum undulatum [97] Inhibits human tumor cell lines A-549, (Rhapontin) SK-OV-3, SK-MEL-2, XF-498 and HCT15 [98] RhapontigeninOHOHOHOCH3 Rheum spp. [96], [97] Inhibits human tumor cell lines A-549, SK-OV-3, SK-MEL-2, XF-498 and HCT15 [98] This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. *R3 = H for all the stilbenes except for oxyresveratrol where R3 = OH; DMBA, 7,12-dimethylbenz[a]anthracene. core structure of 1,1,2-triphenylethylene (which contains the its naturally-occurring analogues as related to colon cancer pre- stilbene skeleton), proved to be highly efficacious for the preven- ventive activity. tion and treatment of breast cancer [14]. A synthetic stilbene, 3′- hydroxystilbene, was markedly more effective than resveratrol in inhibiting the growth of sensitive and resistant leukemia cells Mechanisms of Action of Stilbenes HL60, K562, HUT78, and HUT78B3 [15]. 3,4,5-Trimethoxy-4′- ! bromo-cis-stilbene inhibited human colon cancer cell prolifera- In vitro mechanisms of action of the most representative stil- tion much more effectively than resveratrol, and this trimethoxy- bene, resveratrol, have been extensively discussed in numerous stilbene is considered a good colon cancer chemopreventive or reports and reviews [9], [17], [18], [19]. Resveratrol and other re- chemotherapeutic agent [16]. Although many synthetic stilbene lated stilbenes suppress the proliferation of a wide variety of cul- analogues active against various types of cancer have been gen- tured cancer cells, including colon, prostate, breast, pancreas, erated, this review will mainly focus on resveratrol and some of ovary, melanoma, head and neck, and others [9], [17], [19], [20]. Rimando AMet al. Biological/Chemopreventive Activity of… Planta Med 2008; 74: 1635– 1643 Review 1637 Several key mechanisms of action include inhibition of the tran- mine metabolism. Resveratrol reduced infarct volume after mid- scription factor NF-κB [9], regulation of cytochrome P450 en- dle cerebral artery occlusion in PPARα wild-type mice, while re- zymes [21], [22], activation of nuclear receptors such as estrogen sveratrol failed to protect the brain in PPARα knockout mice, in- receptors (ERs) [23], [24] and peroxisome proliferator-activated dicating that resveratrol protected the brain through a PPARα- receptors (PPARs) [25], [26], [27], inhibition of expression and dependent mechanism [46]. However, using an assay for the ac- activity of inflammation-related enzymes such as cyclooxygena- tivation of endogenous PPARα in H4IIEC3 cells, Rimando et al. ses [17], [19], [28], and regulation of sirtuins [7], [29], [30]. More investigated the activation of PPARα with resveratrol and its details are summarized below. three analogues, pterostilbene, piceatannol, and resveratrol tri- methyl ether, and showed that pterostilbene, but not resveratrol, Growth inhibition and induction of apoptosis by piceatannol, or resveratrol trimethyl ether, acts as a PPARα ago- stilbenes