Antitumor effect of resveratrol oligomers against human cancer cell lines and the molecular mechanism of apoptosis induced by vaticanol C.
Twenty resveratrol (3,5,4'-trihydroxystilbene) (Res) derivatives, which were isolated from stem bark of Vatica rassak (Dipterocarpaceae), were evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. Among them, seven compounds displayed marked cytotoxicity. Vaticanol C (Vat C) as a major component induced a considerable cytotoxicity in all cell lines tested and exhibited growth suppression in colon cancer cell lines at low dose. Vat C caused two cell lines (SW480 and HL60) to induce cell death at four to seven times lower concentrations, compared with Res. The growth suppression by Vat C was found to be due to apoptosis, which was assessed by morphological findings (nuclear condensation and fragmentation) and DNA ladder formation in the colon cancer cell lines. The apoptosis in SW480 colon cancer cells was executed by the activation of caspase-3, which was shown by western blot and apoptosis inhibition assay. Furthermore, the mitochondrial membrane potential of apoptotic SW480 cells after 12 h treatment with Vat C was significantly lost, and concurrently the cytochrome c release and activation of caspase-9 were also detected by western blot analysis. Over-expression of Bcl-2 protein in SW480 cells significantly prevented the cell death induced by Vat C. Taken together, the findings presented here indicate that Vat C induced marked apoptosis in malignant cells mainly by affecting mitochondrial membrane potential.
Ito
Tetsuro
T
Gifu International Institute of Biotechnology, Mitake, Kani-gun, Gifu 505-0116, Japan.
Akao
Yukihiro
Y
Yi
Hong
H
Ohguchi
Kenji
K
Matsumoto
Kenji
K
Tanaka
Toshiyuki
T
Iinuma
Munekazu
M
Nozawa
Yoshinori
Y
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D004789:Enzyme Activation; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; C459559:vaticanol C; D020169:Caspases; D000077185:Resveratrol