Antitumor effects of naturally occurring oligomeric resveratrol derivatives.
This study was designed to evaluate and characterize the molecular basis of antitumor activity of naturally occurring resveratrol (RES; 3,5,4'-trihydroxy-trans-stilbene) derivatives. The compounds were isolated from plants in previous studies and characterized spectroscopically. The antitumor activities of 31 RES derivatives, including dimers, trimers, and tetramers of RES, were evaluated using cell-based assays and validated on a murine model. Several trimeric and a tetrameric stilbenoids induced tumor cell apoptosis or growth arrest of several tumor cell lines with IC50 values (2.8-19.7 μM), significantly lower than that of RES (IC50>70 μM). Using pauciflorol B (PauB) as an example, we showed that the compound induced apoptosis p53 dependently, inducing p53 accumulation and p53-modulated gene expression in cells with wild-type p53, but not in those with nonfunctional p53. Reexpression of p53 in p53-null cells rescued cell death response. In parallel, the MAPK/p38 was activated and critical for PauB-induced killing. Interestingly, activation of p38 in p53 deficient cells was sufficient to drive cells into senescence via the p16-pRb pathway. Finally, PauB dose-dependently inhibited tumor growth on nude mice. Naturally occurring trimeric and tetrameric stilbenoids are potent antitumor agents. Those compounds exert antitumor effect through p53-dependent induction of apoptosis or senescence.
1Nanjing University, 22 Hankou Road, Nanjing, China, 210093. E.L., erguang@nju.edu.cn.
Haishi
H
Qiao
Xiaoqing
X
Chen
Lanfang
L
Xu
Jingjing
J
Wang
Guoyan
G
Zhao
Yayi
Y
Hou
Hui Ming
HM
Ge
Ren-Xiang
RX
Tan
Erguang
E
Li
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019942:Genes, p16; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy; D011108:Polymers / Q000737:chemistry; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D011108:Polymers; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases; D000077185:Resveratrol
apoptosis; p53; senescence; stilbenoid