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

EMBO Molecular Medicine

Qi Zhang²  Shelya X. Zeng²  Yu Zhang¹  Yiwei Zhang²  Derong Ding¹  Qizhuang Ye¹  Samy O. Meroueh¹ 

[1]Department of Biochemistry & Molecular Biology, Indiana University School of Medicine-Simon Cancer Center, Indianapolis, IN, USA

[2]Department of Biochemistry & Molecular Biology and Cancer Center, Tulane University School of Medicine, Louisiana, LA, USA

关键词: apoptosis;    Inauhzin;    p53;    SIRT1;    small molecule inhibitor;   

DOI  :  10.1002/emmm.201100211

来源: Wiley

【 摘 要 】

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.

【 授权许可】

Unknown   
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