tenovin-6 and Colonic-Neoplasms

It has been reported that upregulated SIRT1 (NAD(+)-dependent class III histone deacetylase) deacetylates the p53 protein, represses its function, and allows for tumor cell growth in various cancers. Here we investigated antitumor effects of tenovin-6, a small-molecule inhibitor of SIRT1 and SIRT2, in various colon cancer cell lines. Tenovin-6 induced apoptosis in all five colon cancer cell lines investigated (two cell lines with wild-type p53 and three with mutant p53) regardless of the p53 mutation status. This effect was accompanied by accumulation of death receptor 5 (DR5) in most cell lines. DR5 silencing in HCT116 cells strongly attenuated tenovin-6-induced apoptosis. We investigated the effect of combining tenovin-6 with conventional anticancer agents 5-fluorouracil (5-FU), SN-38 (an active metabolite of irinotecan), and oxaliplatin. Synergistic antitumor effects of tenovin-6 were observed in combination with either 5-FU or oxaliplatin in vitro. The combination of tenovin-6 and oxaliplatin exhibited potent growth inhibition of HCT116 xenograft tumors in vivo. In conclusion, tenovin-6 induced apoptosis in human colon cancer cells through the activation of the DR5 signaling pathway and enhanced the antitumor properties of 5-FU and oxaliplatin. These results may help develop a novel treatment option for colorectal cancer using a SIRT inhibitor.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzamides; Caco-2 Cells; Camptothecin; Colonic Neoplasms; Drug Synergism; Female; Fluorouracil; HCT116 Cells; HT29 Cells; Humans; Irinotecan; Mice; Mice, Inbred BALB C; Mice, Nude; Organoplatinum Compounds; Oxaliplatin; Random Allocation; Receptors, TNF-Related Apoptosis-Inducing Ligand; Sirtuin 1; Sirtuin 2; Sirtuins; Up-Regulation; Xenograft Model Antitumor Assays