The sirtuin inhibitor tenovin-6 upregulates death receptor 5 and enhances cytotoxic effects of 5-fluorouracil and oxaliplatin in colon cancer cells.

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.

journal_name

Oncol Res

journal_title

Oncology research

authors

Ueno T,Endo S,Saito R,Hirose M,Hirai S,Suzuki H,Yamato K,Hyodo I

doi

10.3727/096504013X13854886566598

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

155-64

issue

3

eissn

0965-0407

issn

1555-3906

journal_volume

21

pub_type

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