Antitumor activity of 3,5,4'-trimethoxystilbene in COLO 205 cells and xenografts in SCID mice.

Abstract

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.

• Authors: Min-Hsiung Pan, Jia-Hui Gao, Ching-Shu Lai, Ying-Jan Wang, Wen-Ming Chen, Chih-Yu Lo, Mingfu Wang, Slavik Dushenkov, Chi-Tang Ho
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 47 Issue 3 Pg. 184-96 (Mar 2008) ISSN: 1098-2744 [Electronic] United States
• PMID: 18085528 (Publication Type: Comparative Study, Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2007 Wiley-Liss, Inc.

Chemical References

• 3,4',5-trimethoxystilbene
• Antineoplastic Agents
• Proliferating Cell Nuclear Antigen
• Reactive Oxygen Species
• Stilbenes
• Caspases

Topics

• Adenocarcinoma (drug therapy, pathology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colonic Neoplasms (drug therapy, pathology)
• DNA Fragmentation (drug effects)
• Drug Evaluation, Preclinical
• Enzyme Activation (drug effects)
• Humans
• Immunohistochemistry
• Inhibitory Concentration 50
• Membrane Potentials (drug effects)
• Mice
• Mice, SCID
• Mitochondria (drug effects)
• Molecular Structure
• Proliferating Cell Nuclear Antigen (metabolism)
• Reactive Oxygen Species (metabolism)
• Stilbenes (chemistry, pharmacology)
• Xenograft Model Antitumor Assays (methods)