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.
|Titolo:||The presence of wild type p53 in hematological cancers improves the efficacy of combinational therapy targeting metabolism|
|Parole Chiave:||AMPK; dichloroacetate; metabolism; mutant p53; oxidative phosphorylation; AMP-Activated Protein Kinases; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzoquinones; Cell Cycle Checkpoints; Cell Line, Tumor; Dichloroacetic Acid; Doxorubicin; Drug Synergism; HCT116 Cells; HL-60 Cells; Humans; Lactams, Macrocyclic; Leukemia; Mice; Oxidative Phosphorylation; Transcription, Genetic; Tumor Suppressor Protein p53|
|Settore Scientifico Disciplinare:||Settore MED/06 - Oncologia Medica|
|Data di pubblicazione:||7-ago-2015|
|Digital Object Identifier (DOI):||10.18632/oncotarget.4653|
|Appare nelle tipologie:||01 - Articolo su periodico|