title: Calcium-Dependent Enhancement by Extracellular Acidity of the Cytotoxicity of Mitochondrial Inhibitors against Melanoma.
abstract: Extracellular acidity is a hallmark of cancers and is independent of hypoxia. Because acidity potentiates malignant phenotypes, therapeutic strategies that enhance the targeting of oncogenic mechanisms in an acidic microenvironment should be effective. We report here that drugs which abrogate mitochondrial respiration show enhanced cytotoxicity against melanoma cells in a normoxic but acidic extracellular pH, independent from P53 mutations, BRAF (V600E) mutations, and/or resistance against BRAF inhibitors. Conversely, the cytotoxicity against melanoma cells of mitochondrial inhibitors is impaired by a neutral or alkaline extracellular pH, andin vivosystemic alkalinization with NaHCO3enhanced subcutaneous tumor growth and lung metastasis of B16F10 cells in mice treated with the mitochondrial inhibitor phenformin. Intracellular calcium (Ca2+) was significantly increased in melanoma cells treated with mitochondrial inhibitors at an acidic extracellular pH and an intracellular Ca2+chelator, BAPTA/AM, inhibited cytoplasmic Ca2+as well as melanoma cell death. Surprisingly, ROS scavengers synergized with increased apoptosis in cells treated with mitochondrial inhibitors, suggesting that ROS contributes to cell survival in this context. Notably, the cytotoxic enhancement of mitochondrial inhibitors by acidity was distinct from PGC1alpha-driven mitochondrial addiction, from therapy-induced senescence, and from slow, JARID1B-high-associated cell cycling, all of which have been shown to promote vulnerability to mitochondrial inhibition. These data indicate that extracellular pH profoundly modulates the cytotoxicity of mitochondrial inhibitors against cancer cells.Mol Cancer Ther; 16(5); 936-47. ©2017 AACR.
authors.affiliation: Department of Regenerative Dermatology, Graduate School of Medicine, Osaka University, Osaka, Japan. noguchi@r-derma.med.osaka-u.ac.jp.|Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Fumihito
authors.initials: F
authors.lastname: Noguchi
authors.affiliation: Department of Regenerative Dermatology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Inui
authors.affiliation: Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Clare
authors.initials: C
authors.lastname: Fedele
authors.affiliation: Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.|Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Shackleton
authors.affiliation: Department of Regenerative Dermatology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Itami
mesh_terms: D000143:Acids / Q000737:chemistry; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D004533:Egtazic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D000072258:Tumor Hypoxia / Q000187:drug effects
chemical_list: D000143:Acids; D047428:Protein Kinase Inhibitors; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D002118:Calcium