Tyrosine kinase inhibition in leukemia induces an altered metabolic state sensitive to mitochondrial perturbations.

Autor:	Alvarez-Calderon F; Integrated Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado. School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Gregory MA; School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Pham-Danis C; School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Cancer Biology Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado., DeRyckere D; School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Pediatrics, Division of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Stevens BM; School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Medicine, Section of Hematology, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Zaberezhnyy V; School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Hill AA; School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Pediatrics, Division of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Gemta L; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Kumar A; School of Pharmacy, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Kumar V; School of Pharmacy, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Wempe MF; School of Pharmacy, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Pollyea DA; School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Medicine, Section of Hematology, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Jordan CT; School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Cancer Biology Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Medicine, Section of Hematology, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Serkova NJ; School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Radiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Graham DK; Integrated Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Cancer Biology Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Pediatrics, Division of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Medicine, Section of Hematology, University of Colorado Anschutz Medical Campus, Aurora, Colorado., DeGregori J; Integrated Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Cancer Biology Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Pediatrics, Division of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Medicine, Section of Hematology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. James.DeGregori@ucdenver.edu.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2015 Mar 15; Vol. 21 (6), pp. 1360-72. Date of Electronic Publication: 2014 Dec 29.
DOI:	10.1158/1078-0432.CCR-14-2146
Abstrakt:	Purpose: Although tyrosine kinase inhibitors (TKI) can be effective therapies for leukemia, they fail to fully eliminate leukemic cells and achieve durable remissions for many patients with advanced BCR-ABL(+) leukemias or acute myelogenous leukemia (AML). Through a large-scale synthetic lethal RNAi screen, we identified pyruvate dehydrogenase, the limiting enzyme for pyruvate entry into the mitochondrial tricarboxylic acid cycle, as critical for the survival of chronic myelogenous leukemia (CML) cells upon BCR-ABL inhibition. Here, we examined the role of mitochondrial metabolism in the survival of Ph(+) leukemia and AML upon TK inhibition. Experimental Design: Ph(+) cancer cell lines, AML cell lines, leukemia xenografts, cord blood, and patient samples were examined. Results: We showed that the mitochondrial ATP-synthase inhibitor oligomycin-A greatly sensitized leukemia cells to TKI in vitro. Surprisingly, oligomycin-A sensitized leukemia cells to BCR-ABL inhibition at concentrations of 100- to 1,000-fold below those required for inhibition of respiration. Oligomycin-A treatment rapidly led to mitochondrial membrane depolarization and reduced ATP levels, and promoted superoxide production and leukemia cell apoptosis when combined with TKI. Importantly, oligomycin-A enhanced elimination of BCR-ABL(+) leukemia cells by TKI in a mouse model and in primary blast crisis CML samples. Moreover, oligomycin-A also greatly potentiated the elimination of FLT3-dependent AML cells when combined with an FLT3 TKI, both in vitro and in vivo. Conclusions: TKI therapy in leukemia cells creates a novel metabolic state that is highly sensitive to particular mitochondrial perturbations. Targeting mitochondrial metabolism as an adjuvant therapy could therefore improve therapeutic responses to TKI for patients with BCR-ABL(+) and FLT3(ITD) leukemias. (©2014 American Association for Cancer Research.)
Databáze:	MEDLINE
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