Hindawi Publishing Corporation Oxidative Medicine and Cellular Longevity Volume 2014, Article ID 765832, 9 pages http://dx.doi.org/10.1155/2014/765832 Review Article Resveratrol Oligomers for the Prevention and Treatment of Cancers You-Qiu Xue,1 Jin-Ming Di,2 Yun Luo,2 Ke-Jun Cheng,3 Xing Wei,1 and Zhi Shi1 1 Department of Cell Biology & Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510630, China 2 Department of Urology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China 3 Chemical Biology Center, Lishui Institute of Agricultural Sciences, Lishui, Zhejiang 32300, China Correspondence should be addressed to Xing Wei; [email protected] and Zhi Shi; [email protected] Received 15 January 2014; Accepted 12 February 2014; Published 23 March 2014 Academic Editor: Xiaoqian Chen Copyright © 2014 You-Qiu Xue et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Resveratrol (3,4 ,5-trihydroxystilbene) is a naturally derived phytoalexin stilbene isolated from grapes and other plants, playing an important role in human health and is well known for its extensive bioactivities, such as antioxidation, anti-inflammatory, anticancer. In addition to resveratrol, scientists also pay attention to resveratrol oligomers, derivatives of resveratrol, which are characterized by the polymerization of two to eight, or even more resveratrol units, and are the largest group of oligomeric stilbenes. Resveratrol oligomers have multiple beneficial properties, of which some are superior in activity, stability, and selectivity compared with resveratrol. The complicated structures and diverse biological activities are of significant interest for drug research and development and may provide promising prospects as cancer preventive and therapeutical agents. This review presents an overview on preventive or anticancer properties of resveratrol oligomers. 1. Introduction and beverages such as mulberries, peanuts, grapes, and red wine [8]. Resveratrol can be classified either as a polyphenol There are growing interests in using natural compounds as orstilbeneandisproducedbyplantstoprotectthemselves potential cancer therapeutics or cancer preventive agents for against damage or infection in response to stresses such as human diseases. Lots of epidemiological data illustrate that heat, insects, bacteria, and fungus [9]. During the last decade, there is a significant correlation between dietary intake and resveratrol attracted increasing attention due to its preventive incidence of many kinds of cancers, and the incidence of potential towards the most severe contemporary human cancertrendstoraiseyearbyyearintheworldduetochanges diseases, such as cancer, neurodegenerative disease, vascular in modern lifestyles and diet custom [1–3]. Due to the unsatis- disease, cardiovascular disease, and aging [10–13]. Resveratrol fied effectiveness of current cancer chemotherapy, there isan wasreportedtomakeagreatinfluenceontheprocessof urgent need of new anticancer drugs with high efficiency and carcinogenesis by affecting cancer initiation and progression lowtoxicity.Fightingcancerswithnovelnaturalproducts, [8, 14]. Resveratrol was shown to exert a different inhibition to especially those extracted from plants-derived diet, seems to various human tumors cells by in vitro experiments through be a fascinating strategy. Furthermore, in vivo and in vitro multiple mechanisms as well as different in vivo animal studies show that many dietary substances have anticancer models [15, 16]. In addition, there was no significant toxicity properties [4, 5]. Resveratrol and its oligomers belong to such to mice after the daily oral administration of high doses of kind of dietary substances. resveratrol for 28 days [17]. Resveratrol (3,4 ,5-trihydroxystilbene) was first isolated Chemical structure analysis showed that resveratrol was a from the roots of white hellebore, Veratrum grandiflorum polyphenol biphenyl, and multiple hydroxyl groups affected O. Loes [6], found in at least 72 plant species including 12 its biological activities as well as cis-ortrans-structures [18, families and 31 genera [7], and widely exist in edible foods 19]. In addition to resveratrol, scientists also focus on its 2 Oxidative Medicine and Cellular Longevity Resveratrol -viniferin -viniferin Heimiol A HO HO HO H O OH HO H H OH O OH O H HO HO H HO H H H OH OH OH OH OH OH HO OH R Pallidol Balanocarpol -H Malibatol A Malibatol B Ampelopsin -H OH HO HO HO HO H HO O OH O OH O OH H OH HO HO HO H H HO H OH OH HO H R H OH OH OH H OH OH OH OH OH OH (a) R Suffruticosol A -H -viniferin Miyabenol C Gnetin H Suffruticosol B -H OH OH OH H HO OH O H H OH HO OH O O H OH O H HO O H HO OH H H H H HO H HO R OH HH O HO H H H H OH OH O OH O H H OH OH OH HO OH HO OH OH OH (b) Vaticanol C Kobophenol A Hopeaphenol HO OH HO OH HO HO H H OH HO O OH OH O OH H H H H HO HO H H OH H OH H H H H H OH H H HO HO O O H H HO O H OH OH OH HO H H H OH OH HO O OH HO OH H OH OH (c) Figure 1: Structure of selected resveratrol oligomers. (a) Resveratrol and resveratrol dimers. (b) Resveratrol trimers. (c) Resveratrol tetramers. Oxidative Medicine and Cellular Longevity 3 Antibacterial and antifungal activity Modulation of lipid metabolism Antioxidant activity CNS-related activity Resveratrol Anticancer activity oligomers Estrogenic activity Anti-inflammatory activity Antithrombotic Effect of cardiovascular activity protection Figure 2: Bioactivities of resveratrol oligomers. Pallidol, MRP1 vaticanol C, PKC -Viniferin Tyrosinase PI3K MEK -Viniferin -Viniferin Vaticanol C -Viniferin SK1 Akt Erk vaticanol C, pallidol DNA Balanocarpol Bad PARP Nrf2 -Viniferin CYP-1A1, -Viniferin -1B1, -2B6 NF-B HO-1 -Viniferin Cyt C Vaticanol C p38 -Viniferin Caspase-2, -8 -Viniferin COX I -Viniferin NO -Viniferin Caspase-3, Vaticanol C -8, -9 Vaticanol C MMP1 ROS -Viniferin, pallidol Bcl-2 Vaticanol C Survivin Vaticanol C PARP Vaticanol C, balanocarpol Figure 3: The potential molecular mechanism of resveratrol oligomers for the prevention and treatment of cancer. derivatives, such as resveratrol oligomers. Resveratrol oli- review, we summarize the recent progresses of the preventive gomers are characterized by the polymerization of two to and anticancer activities as well as related mechanisms of eight resveratrol units and even more and are the largest resveratrol oligomers (Tables 1 and 2 and Figure 3)andcon- group of oligomeric stilbenes (Figure 1)[20]. Resveratrol template their prospects as preventive and anticancer agents. oligomers polyphenols were mainly isolated from five plant families, namely, Vitaceae, Leguminosae, Gnetaceae, Dipte- rocarpaceae, and Cyperaceae [20–23]. In addition, resveratrol 2. Resveratrol Dimers oligomers were recognized as fungal detoxification products Resveratrol dimers are formed from two resveratrol mono- of resveratrol metabolism. These oligomers were found to mers by oxidation reaction. Series of combination of mono- exhibit widely biological activities, such as antibacterial, mers form different dimers which possess various activities. antifungal, anticancer, anti-HIV, and antioxidant activities (Figure 2)[24, 25]. Their intricate structures and diverse bio- logical activities are of significant interests for drug research 2.1. -Viniferin. -Viniferin, first isolated from Vitis vinifera anddevelopmentandmayprovidepromisingprospectsas (Vitaceae), is classified as a model for its biosynthesis cancer preventive and therapeutical agents [26]. Although from resveratrol [21]. Similar to resveratrol, -viniferin also lots of studies showed various biochemical and pharma- attracted attention as a phytoalexin and was reported to have cological properties of resveratrol oligomers, so far there antifungal, antibacterial, and antiviral activities [59]. To date, is no systematic review about these compounds. In this many studies of -viniferin are about the antioxidant and 4 Oxidative Medicine and Cellular Longevity Table 1: The anticancer activities of resveratrol oligomers. Resveratrol Cell lines and inhibition References oligomers C6+++ ,HepG2+,HeLa++,MCF-7+,HT-29+ -Viniferin [27–29] U266++,RPMI8226++, Jurkat+,K562++,U937++ Pallidol A549+++ [30] Balanocarpol P-388++ [31, 32] HL-60+++,MCF-7+,HepG2+,A549+,P-388+, -Viniferin [22, 33] HCT-116++,HT-29++, Caco-2++ A54+++, NCI-H 446+++, U266+++,RPMI8226+++ Miyabenol C [22, 30, 34] Jurkat++,K562+++,U937+++ SW-480+++,DLD-1+,CoLo201+,PC-3+,LNCaP++ Vaticanol C [10, 35–37] SH-SY5Y++,HL-60+++,K562+,U937++ Kobophenol A A549+ [30] Hopeaphenol SW-480+,HL-60+,P-388+++ [10, 28] +++ ++ + The plus signs indicated the ability to against human cancer cell lines: IC50 values less of 20 M; IC50 values range 20 Mto50 M; IC50 values of 50 M to 100 M. Table 2: The potential targets of resveratrol oligomers involved in apoptosis, cell proliferation, and inflammation. Resveratrol Cell cycle Inhibition of proliferation and Induction of apoptosis References oligomers arrest inflammation ROS↓,Caspase-2,8↑,CYP1A1↓, -Viniferin G2/M Nrf2↑,HO-1↑,PI3K↑,p38↑ [38–44] CYP1B1↓,CYP2B6↓ Pallidol — ROS↓ PKC↓,ERK↓ [45–48] Balanocarpol — Cleaved PARP↑ DNA↓,SK1↓ [49, 50] PKC↓, Tyrosinase↓, MRP1↓,COΧ I↓, -viniferin S — [45, 51–55] NO↓,STAT1↓,ERK↓, IFN-↓ [20, 22, 34, Miyabenol C G0/G1 — PKC↓ 56] [10, 26, 32, Caspase-3, 8, 9↑,Bad↑,CytochromeC↑, Vaticanol C — MEK↓,Akt↓ 35– Bcl-2↑,