Open AccessA small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53
Author(s) -
Zhang Qi,
Zeng Shelya X.,
Zhang Yu,
Zhang Yiwei,
Ding Derong,
Ye Qizhuang,
Meroueh Samy O.,
Lu Hua
Publication year - 2012
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201100211
Subject(s) - mdm2 , mdmx , apoptosis , acetylation , cancer research , suppressor , cell growth , biology , in vitro , dna damage , cancer , microbiology and biotechnology , dna , biochemistry , gene , genetics
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.