Antitumor activity of 3,5,4'-trimethoxystilbene in COLO 205 cells and xenografts in SCID mice.
Resveratrol (R-3), a trihydroxy trans-stilbene from grape, inhibits multistage carcinogenesis in animal models. Here we report that 3,5,4'-trimethoxystilbene (MR-3), the permethylated derivative of R-3 was more potent against the growth of human cancer cells (HT-29, PC-3, COLO 205) with estimated IC(50) values of 81.31,42.71, and 6.25 microM, respectively. We further observed that MR-3 induced apoptosis in COLO 205 cells through modulation of mitochondrial functions regulated by reactive oxygen species (ROS). ROS generation occurs in the early stages of MR-3-induced apoptosis, preceding cytochrome-c release, caspase activation, and DNA fragmentation. Significant therapeutic effects were demonstrated in vivo by treating severe combined immune deficiency (SCID) mice bearing COLO 205 tumor xenografts with MR-3 (50 mg/kg ip). Assays on DNA fragmentation and caspase activation were performed and demonstrated that apoptosis occurred in tumor tissues treated with MR-3. The appearance of apoptotic cells, as shown by Hematoxylin and Eosin (H&E) staining, and an increase in p21 and decrease in proliferating cell nuclear antigen (PCNA) protein by immuno-histochemistry were observed in tumor tissues under MR-3 treatment. Our study identifies the novel mechanisms of the antitumor effects of MR-3 and indicates that these results may have significant applications for cancer chemotherapy.
Pan
Min-Hsiung
MH
Department of Seafood Science, National Kaohsiung Marine University, Nan-Tzu, Kaohsiung, Taiwan.
Gao
Jia-Hui
JH
Lai
Ching-Shu
CS
Wang
Ying-Jan
YJ
Chen
Wen-Ming
WM
Lo
Chih-Yu
CY
Wang
Mingfu
M
Dushenkov
Slavik
S
Ho
Chi-Tang
CT
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053938:DNA Fragmentation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects; D015394:Molecular Structure; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
C497286:3,4',5-trimethoxystilbene; D000970:Antineoplastic Agents; D018809:Proliferating Cell Nuclear Antigen; D017382:Reactive Oxygen Species; D013267:Stilbenes; D020169:Caspases