RRC ID 44904
Author Ueno T, Endo S, Saito R, Hirose M, Hirai S, Suzuki H, Yamato K, Hyodo I.
Title The sirtuin inhibitor tenovin-6 upregulates death receptor 5 and enhances cytotoxic effects of 5-fluorouracil and oxaliplatin in colon cancer cells.
Journal Oncol Res
Abstract 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.
Volume 21(3)
Pages 155-64
Published 2013-1-1
DOI 10.3727/096504013X13854886566598
PMID 24512730
MeSH Animals Antineoplastic Combined Chemotherapy Protocols / pharmacology* Apoptosis / drug effects Benzamides / administration & dosage Benzamides / pharmacology* Caco-2 Cells Camptothecin / administration & dosage Camptothecin / analogs & derivatives Camptothecin / pharmacology Colonic Neoplasms / drug therapy* Colonic Neoplasms / metabolism Colonic Neoplasms / pathology Drug Synergism Female Fluorouracil / administration & dosage Fluorouracil / pharmacology* HCT116 Cells HT29 Cells Humans Irinotecan Mice Mice, Inbred BALB C Mice, Nude Organoplatinum Compounds / administration & dosage Organoplatinum Compounds / pharmacology* Oxaliplatin Random Allocation Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism* Sirtuin 1 / antagonists & inhibitors Sirtuin 2 / antagonists & inhibitors Sirtuins / antagonists & inhibitors* Sirtuins / metabolism Up-Regulation / drug effects Xenograft Model Antitumor Assays
IF 4.949
Times Cited 18
Human and Animal Cells MRC-5