Reactivation of Mutant p53 and Induction of Apoptosis in Human Tumor Cells by Maleimide Analogs

Vladimir J.N Bykov,Natalia Issaeva,Nicole Zache,Alexandre Shilov,Monica Hultcrantz,Jan Bergman,Galina Selivanova,Klas G Wiman

doi:10.1074/jbc.m501664200

Vladimir J.N Bykov, Natalia Issaeva + Show 6 more

Open Access

https://doi.org/10.1074/jbc.m501664200

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Abstract

Reactivation of mutant p53 is likely to provide important benefits for treatment of chemotherapy- and radiotherapy-resistant tumors. We demonstrate here that the maleimide-derived molecule MIRA-1 can reactivate DNA binding and preserve the active conformation of mutant p53 protein in vitro and restore transcriptional transactivation to mutant p53 in living cells. MIRA-1 induced mutant p53-dependent cell death in different human tumor cells carrying tetracycline-regulated mutant p53. The structural analog MIRA-3 showed antitumor activity in vivo against human mutant p53-carrying tumor xenografts in SCID mice. The MIRA scaffold is a novel lead for the development of anticancer drugs specifically targeting mutant p53.

Highlights

The p53 tumor suppressor responds to various types of cellular stress, e.g. DNA damage, hypoxia, and oncogenic signaling, and triggers cell cycle arrest, apoptosis, or senescence [1]
Mutant p53-dependent Growth Suppression by MIRA-1—We previously screened the Diversity set of low molecular weight compounds from NCI, National Institutes of Health using p53null Saos-2 osteosarcoma cells carrying tetracycline-regulated His273 mutant p53 (Tet-off) and the WST-1 cell proliferation assay
This led to the identification of PRIMA-1, a quinuclidinone that inhibits growth of human tumor cells in a mutant p53-dependent manner in vitro and in vivo [18]

Summary

Introduction

The p53 tumor suppressor responds to various types of cellular stress, e.g. DNA damage, hypoxia, and oncogenic signaling, and triggers cell cycle arrest, apoptosis, or senescence [1] This is achieved through transcriptional transactivation of specific target genes carrying p53 DNA binding motifs [1, 2]. We have previously screened a chemical library from the National Cancer Institute and identified PRIMA-1, a compound that induces mutant p53-dependent apoptosis and restores native conformation, DNA binding, and transcriptional transactivation to mutant p53, and inhibits tumor growth in vivo [18]. We describe a novel class of low molecular weight compounds that are structurally different from PRIMA-1 but show similar capacity to restore wild-type conformation and function to mutant p53, and induce tumor cell death in a mutant p53-dependent manner

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