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

79 Citations (Scopus)

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
StatePublished - Jan 1 2011

Fingerprint

Apoptosis
Neoplasms
MCF-7 Cells
Preclinical Drug Evaluations
Cell Survival
Gene Expression
Growth
Proteins
nutlin 3
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A small-molecule inhibitor of MDMX activates p53 and induces apoptosis. / Wang, Hongbo; Ma, Xujun; Ren, Shumei; Buolamwini, John K.; Yan, Chunhong.

In: Molecular cancer therapeutics, Vol. 10, No. 1, 01.01.2011, p. 69-79.

Research output: Contribution to journalArticle

Wang, Hongbo ; Ma, Xujun ; Ren, Shumei ; Buolamwini, John K. ; Yan, Chunhong. / A small-molecule inhibitor of MDMX activates p53 and induces apoptosis. In: Molecular cancer therapeutics. 2011 ; Vol. 10, No. 1. pp. 69-79.
@article{c3764fd98d174630ae77cf51f91c9d2e,
title = "A small-molecule inhibitor of MDMX activates p53 and induces apoptosis",
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.",
author = "Hongbo Wang and Xujun Ma and Shumei Ren and Buolamwini, {John K.} and Chunhong Yan",
year = "2011",
month = "1",
day = "1",
doi = "10.1158/1535-7163.MCT-10-0581",
language = "English (US)",
volume = "10",
pages = "69--79",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "1",

}

TY - JOUR

T1 - A small-molecule inhibitor of MDMX activates p53 and induces apoptosis

AU - Wang, Hongbo

AU - Ma, Xujun

AU - Ren, Shumei

AU - Buolamwini, John K.

AU - Yan, Chunhong

PY - 2011/1/1

Y1 - 2011/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=78751533820&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78751533820&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-10-0581

DO - 10.1158/1535-7163.MCT-10-0581

M3 - Article

C2 - 21075910

AN - SCOPUS:78751533820

VL - 10

SP - 69

EP - 79

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 1

ER -