title: Synergistic effects of ion transporter and MAP kinase pathway inhibitors in melanoma.
abstract: New therapies are required for melanoma. Here, we report that multiple cardiac glycosides, including digitoxin and digoxin, are significantly more toxic to human melanoma cells than normal human cells. This reflects on-target inhibition of the ATP1A1 Na(+)/K(+) pump, which is highly expressed by melanoma. MEK inhibitor and/or BRAF inhibitor additively or synergistically combined with digitoxin to induce cell death, inhibiting growth of patient-derived melanomas in NSG mice and synergistically extending survival. MEK inhibitor and digitoxin do not induce cell death in human melanocytes or haematopoietic cells in NSG mice. In melanoma, MEK inhibitor reduces ERK phosphorylation, while digitoxin disrupts ion gradients, altering plasma membrane and mitochondrial membrane potentials. MEK inhibitor and digitoxin together cause intracellular acidification, mitochondrial calcium dysregulation and ATP depletion in melanoma cells but not in normal cells. The disruption of ion homoeostasis in cancer cells can thus synergize with targeted agents to promote tumour regression in vivo.
authors.affiliation: Department of Pediatrics, Children's Research Institute, Dallas, Texas 75390, USA.
authors.forename: Ugur
authors.identifier: 0000-0003-3785-5275
authors.initials: U
authors.lastname: Eskiocak
authors.affiliation: Department of Pediatrics, Children's Research Institute, Dallas, Texas 75390, USA.
authors.forename: Vijayashree
authors.initials: V
authors.lastname: Ramesh
authors.affiliation: Department of Pediatrics, Children's Research Institute, Dallas, Texas 75390, USA.|Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Gill
authors.affiliation: Department of Pediatrics, Children's Research Institute, Dallas, Texas 75390, USA.
authors.forename: Zhiyu
authors.identifier: 0000-0001-6308-6997
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Pediatrics, Children's Research Institute, Dallas, Texas 75390, USA.
authors.forename: Stacy W
authors.initials: SW
authors.lastname: Yuan
authors.affiliation: Department of Pediatrics, Children's Research Institute, Dallas, Texas 75390, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Vandergriff
authors.affiliation: Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.|Sir Peter MacCallum Department of Oncology and Department of Pathology, University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
authors.forename: Mark
authors.identifier: 0000-0002-7673-4655
authors.initials: M
authors.lastname: Shackleton
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109-2216, USA.
authors.forename: Elsa
authors.initials: E
authors.lastname: Quintana
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109-2216, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Johnson
authors.affiliation: Department of Pediatrics, Children's Research Institute, Dallas, Texas 75390, USA.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.affiliation: Department of Pediatrics, Children's Research Institute, Dallas, Texas 75390, USA.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas Texas 75390, USA.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Morrison
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004074:Digitoxin / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008544:Melanocytes; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D004074:Digitoxin; D048369:MAP Kinase Kinase 1; C499076:ATP1A1 protein, human; D000254:Sodium-Potassium-Exchanging ATPase