Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs

J Biol Chem. 2005 Aug 26;280(34):30384-91. doi: 10.1074/jbc.M501664200. Epub 2005 Jul 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Separation
  • DNA / chemistry
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Glutathione Transferase / metabolism
  • Humans
  • Maleimides / pharmacology*
  • Mice
  • Mice, SCID
  • Microscopy, Fluorescence
  • Models, Chemical
  • Mutation
  • Neoplasm Transplantation
  • Neoplasms / drug therapy*
  • Neoplasms / genetics*
  • Plasmids / metabolism
  • Protein Binding
  • Protein Conformation
  • Tetracycline / metabolism
  • Transcriptional Activation
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Protein p53 / physiology*

Substances

  • Antineoplastic Agents
  • Maleimides
  • Tumor Suppressor Protein p53
  • maleimide
  • DNA
  • Glutathione Transferase
  • Tetracycline