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 Meroueh, Hua Lu

Research output: Contribution to journalArticle

50 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)298-312
Number of pages15
JournalEMBO Molecular Medicine
Volume4
Issue number4
DOIs
StatePublished - Apr 2012

Fingerprint

Growth
Neoplasms
Apoptosis
HCT116 Cells
SCID Mice
Ubiquitination
Acetylation
10-(2-(5H-(1,2,4)triazino(5,6-b)indol-3-ylthio)butanoyl)-10H-phenothiazine
Heterografts
DNA Damage
Cell Proliferation
Therapeutics

Keywords

  • Apoptosis
  • Inauhzin
  • P53
  • SIRT1
  • Small molecule inhibitor

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53. / Zhang, Qi; Zeng, Shelya X.; Zhang, Yu; Zhang, Yiwei; Ding, Derong; Ye, Qizhuang; Meroueh, Samy; Lu, Hua.

In: EMBO Molecular Medicine, Vol. 4, No. 4, 04.2012, p. 298-312.

Research output: Contribution to journalArticle

Zhang, Qi ; Zeng, Shelya X. ; Zhang, Yu ; Zhang, Yiwei ; Ding, Derong ; Ye, Qizhuang ; Meroueh, Samy ; Lu, Hua. / A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53. In: EMBO Molecular Medicine. 2012 ; Vol. 4, No. 4. pp. 298-312.
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