title: Redox-related antimelanoma activity of ATN-224.
abstract: Melanoma cells characteristically produce increased levels of reactive oxygen species (ROS) because of the metal-binding properties of melanin and loss of structural integrity of the melanosome. Agents that deplete gluthathione or inhibit superoxide dismutase, thereby blocking ROS scavenging mechanisms, may be selectively toxic to melanoma. To determine whether the inhibition of ROS scavenging could potentiate alkylator activity, we evaluated the activity of tetrathiomolybdate (ATN-224), a superoxide dismutase inhibitor, alone and in combination with temozolomide, on five melanoma cell lines. We also determined whether the ATN-224 would act synergistically with other agents that interfere with ROS scavenging. We found that the combination of ATN-224 and temozolomide generally exhibited additive cytotoxic effects on the cell lines tested. ATN-224 acted synergistically with buthionine sulfoximine, an agent that causes gluthathione depletion. Combinations of ATN-224 with arsenic trioxide, which may deplete glutathione, or disulfiram, an agent that interferes with recycling of glutathione, were antagonistic. These data suggest that strategically tailoring combination regimens that include ATN-224 and target ROS may be a viable approach to advance the treatment of melanoma.
authors: Clinical Pharmacology and Developmental Therapeutics, University of California Irvine Chao Family Comprehensive Cancer Center, Orange, California, USA.
authors: Valerie
authors: V
authors: Trapp
authors: Kristy
authors: K
authors: Lee
authors: Fernando
authors: F
authors: Doñate
authors: Andrew P
authors: AP
authors: Mazar
authors: John P
authors: JP
authors: Fruehauf
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008543:Melanins / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D008982:Molybdenum / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010087:Oxides / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D004791:Enzyme Inhibitors; D008543:Melanins; D010087:Oxides; D017382:Reactive Oxygen Species; D019328:Buthionine Sulfoximine; D003606:Dacarbazine; D008982:Molybdenum; C020809:tetrathiomolybdate; D013482:Superoxide Dismutase; D005978:Glutathione; D000077237:Arsenic Trioxide; D004221:Disulfiram; D000077204:Temozolomide