The presence of wild type p53 in hematological cancers improves the efficacy of combinational therapy targeting metabolism

Nerea Allende-Vega, Ewelina Krzywinska, Stefania Orecchioni, Nuria Lopez-Royuela, Francesca Reggiani, Giovanna Talarico, Jean François Rossi, Rodrigue Rossignol, Yosr Hicheri, Guillaume Cartron, Francesco Bertolini, Martin Villalba

Research output: Contribution to journalArticlepeer-review

Abstract

Manipulation of metabolic pathways in hematological cancers has therapeutic potential. Here, we determined the molecular mechanism of action of the metabolic modulator dichloroacetate (DCA) in leukemic cells. We found that DCA induces the AMP-activated protein kinase (AMPK)/p53 pathway with increased efficacy in tumors expressing wild type (wt p53). Clinically relevant, low concentrations of doxorubicin synergize in vitro and in vivo with DCA to further enhance p53 activation and to block tumor progression. Leukemia cell lines and primary leukemic cells containing mutant p53 are resistant to the above-described combination approach. However, DCA synergized with the Hsp90 inhibitor 17-AAG to specifically eliminate these cells. Our studies strongly indicate that depending on the p53 status, different combination therapies would provide better treatment with decreased side effects in hematological cancers.

Original languageEnglish
Pages (from-to)19228-19245
Number of pages18
JournalOncotarget
Volume6
Issue number22
Publication statusPublished - 2015

Keywords

  • AMPK
  • Dichloroacetate
  • Metabolism
  • Mutant p53
  • Oxidative phosphorylation

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'The presence of wild type p53 in hematological cancers improves the efficacy of combinational therapy targeting metabolism'. Together they form a unique fingerprint.

Cite this