期刊
EMBO MOLECULAR MEDICINE
卷 4, 期 4, 页码 298-312出版社
WILEY
DOI: 10.1002/emmm.201100211
关键词
apoptosis; Inauhzin; p53; SIRT1; small molecule inhibitor
资金
- CTSI
- NIH-NCI [CA127724, CA095441, CA129828]
- NIH
Although similar to 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.
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