The presence of wild type p53 in hematological cancers improves the efficacy of combinational therapy targeting metabolism
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Nerea Allende-Vega1,*, Ewelina Krzywinska1,*, Stefania Orecchioni2, Nuria Lopez-Royuela1, Francesca Reggiani2, Giovanna Talarico2, Jean-François Rossi3, Rodrigue Rossignol4,5, Yosr Hicheri3, Guillaume Cartron3, Francesco Bertolini2, Martin Villalba1,6
1INSERM U1183, Université de Montpellier 1, UFR Médecine, Montpellier, France
2Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy
3Département d'Hématologie Clinique, CHU Montpellier, Université Montpellier 1, Montpellier, France
4Laboratoire Maladies Rares: Génétique et Métabolisme (MRGM), Université de Bordeaux, Bordeaux, France
5Cellomet, Amélie Rabat-Léon, Bordeaux, France
6Institute for Regenerative Medicine and Biotherapy (IRMB), CHU Montpellier, Montpellier, France
*These authors have contributed equally to this work
Martin Villalba, e-mail: [email protected]
Nerea Allende-Vega, e-mail: [email protected]
Keywords: metabolism, oxidative phosphorylation, dichloroacetate, mutant p53, AMPK
Received: January 29, 2015 Accepted: July 20, 2015 Published: July 30, 2015
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.
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