title: The presence of wild type p53 in hematological cancers improves the efficacy of combinational therapy targeting metabolism.
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.
authors.affiliation: INSERM U1183, Université de Montpellier 1, UFR Médecine, Montpellier, France.
authors.forename: Nerea
authors.initials: N
authors.lastname: Allende-Vega
authors.affiliation: INSERM U1183, Université de Montpellier 1, UFR Médecine, Montpellier, France.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Krzywinska
authors.affiliation: Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Orecchioni
authors.affiliation: INSERM U1183, Université de Montpellier 1, UFR Médecine, Montpellier, France.
authors.forename: Nuria
authors.initials: N
authors.lastname: Lopez-Royuela
authors.affiliation: Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Reggiani
authors.affiliation: Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Talarico
authors.affiliation: Département d'Hématologie Clinique, CHU Montpellier, Université Montpellier I, Montpellier, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Rossi
authors.affiliation: Laboratoire Maladies Rares : Génétique et Métabolisme (MRGM), Université de Bordeaux, Bordeaux, France.|Cellomet, Amélie Rabat-Léon, Bordeaux, France.
authors.forename: Rodrigue
authors.initials: R
authors.lastname: Rossignol
authors.affiliation: Département d'Hématologie Clinique, CHU Montpellier, Université Montpellier I, Montpellier, France.
authors.forename: Yosr
authors.initials: Y
authors.lastname: Hicheri
authors.affiliation: Département d'Hématologie Clinique, CHU Montpellier, Université Montpellier I, Montpellier, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Cartron
authors.affiliation: Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertolini
authors.affiliation: INSERM U1183, Université de Montpellier 1, UFR Médecine, Montpellier, France.|Institute for Regenerative Medicine and Biotherapy (IRMB), CHU Montpellier, Montpellier, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Villalba
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D016227:Benzoquinones / Q000008:administration & dosage; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D003999:Dichloroacetic Acid / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D045325:HCT116 Cells; D018922:HL-60 Cells; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010085:Oxidative Phosphorylation; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D047029:Lactams, Macrocyclic; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C112765:tanespimycin; D004317:Doxorubicin; D003999:Dichloroacetic Acid; D055372:AMP-Activated Protein Kinases
keywords: AMPK; dichloroacetate; metabolism; mutant p53; oxidative phosphorylation