Embo Molecular Medicine 2012-04-01

A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53.

Qi Zhang, Shelya X Zeng, Yu Zhang, Yiwei Zhang, Derong Ding, Qizhuang Ye, Samy O Meroueh, Hua Lu

Index: EMBO Mol. Med. 4(4) , 298-312, (2012)

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Abstract

Although ∼50% of all types of human cancers harbour wild-type TP53, this p53 tumour suppressor is often deactivated through a concerted action by its abnormally elevated suppressors, MDM2, MDMX or SIRT1. Here, we report a novel small molecule Inauhzin (INZ) that effectively reactivates p53 by inhibiting SIRT1 activity, promotes p53-dependent apoptosis of human cancer cells without causing apparently genotoxic stress. Moreover, INZ stabilizes p53 by increasing p53 acetylation and preventing MDM2-mediated ubiquitylation of p53 in cells, though not directly in vitro. Remarkably, INZ inhibits cell proliferation, induces senescence and tumour-specific apoptosis, and represses the growth of xenograft tumours derived from p53-harbouring H460 and HCT116 cells without causing apparent toxicity to normal tissues and the tumour-bearing SCID mice. Hence, our study unearths INZ as a novel anti-cancer therapeutic candidate that inhibits SIRT1 activity and activates p53.Copyright © 2012 EMBO Molecular Medicine.