A small-molecule inhibitor of MDMX activates p53 and induces apoptosis

Hongbo Wang, Xujun Ma, Shumei Ren, John K. Buolamwini, Chunhong Yan

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

The p53 inactivation caused by aberrant expression of its major regulators (e.g., MDM2 and MDMX) contributes to the genesis of a large number of human cancers. Recent studies have shown that restoration of p53 activity by counteracting p53 repressors is a promising anticancer strategy. Although agents (e.g., nutlin-3a) that disrupt MDM2-p53 interaction can inhibit tumor growth, they are less effective in cancer cells that express high levels of MDMX. MDMX binds to p53 and can repress the tumor suppressor function of p53 through inhibiting its trans-activation activity and/or destabilizing the protein. Here we report the identification of a benzofuroxan derivative [7-(4-methylpiperazin- 1-yl)-4-nitro-1-oxido-2,1,3-benzoxadiazol-1-ium, NSC207895] that could inhibit MDMX expression in cancer cells through a reporter-based drug screening. Treatments of MCF-7 cells with this small-molecule MDMX inhibitor activated p53, resulting in elevated expression of proapoptotic genes (e.g., PUMA, BAX, and PIG3). Importantly, this novel small-molecule p53 activator caused MCF-7 cells to undergo apoptosis and acted additively with nutlin-3a to activate p53 and decrease the viability of cancer cells. These results thus show that small molecules targeting MDMX expression would be of therapeutic benefits.

Original languageEnglish (US)
Pages (from-to)69-79
Number of pages11
JournalMolecular cancer therapeutics
Volume10
Issue number1
DOIs
Publication statusPublished - Jan 1 2011
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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