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.

• Authors: Takunori Ueno, Shinji Endo, Rie Saito, Mitsuaki Hirose, Sachiko Hirai, Hideo Suzuki, Kenji Yamato, Ichinosuke Hyodo
• Journal: Oncology research (Oncol Res) Vol. 21 Issue 3 Pg. 155-64 ( 2013) ISSN: 1555-3906 [Electronic] United States
• PMID: 24512730 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Organoplatinum Compounds
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• tenovin-6
• Oxaliplatin
• Irinotecan
• SIRT1 protein, human
• SIRT2 protein, human
• Sirtuin 1
• Sirtuin 2
• Sirtuins
• Fluorouracil
• Camptothecin

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Benzamides (administration & dosage, pharmacology)
• Caco-2 Cells
• Camptothecin (administration & dosage, analogs & derivatives, pharmacology)
• Colonic Neoplasms (drug therapy, metabolism, pathology)
• Drug Synergism
• Female
• Fluorouracil (administration & dosage, pharmacology)
• HCT116 Cells
• HT29 Cells
• Humans
• Irinotecan
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Organoplatinum Compounds (administration & dosage, pharmacology)
• Oxaliplatin
• Random Allocation
• Receptors, TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Sirtuin 1 (antagonists & inhibitors)
• Sirtuin 2 (antagonists & inhibitors)
• Sirtuins (antagonists & inhibitors, metabolism)
• Up-Regulation (drug effects)
• Xenograft Model Antitumor Assays