title: Neurotoxicity Associated with Platinum-Based Anti-Cancer Agents: What are the Implications of Copper Transporters?
abstract: Platinum-based anti-cancer agents, which include cisplatin, carboplatin and oxaliplatin, are an important class of drugs used in clinical setting to treat a variety of cancers. The cytotoxic efficacy of these drugs is mediated by the formation of inter-strand and intrastrand crosslinks, or platinum adducts on nuclear DNA. There is also evidence demonstrating that mitochondrial DNA is susceptible to platinum-adduct damage in dorsal root ganglia neurons. Although all platinum-based agents form similar DNA adducts, they are quite different in terms of activation, systemic toxicity and tolerance. Platinum-based agents are well known for their neurotoxicity and gastrointestinal side-effects which are major causes for dose limitation and treatment discontinuation compromising the efficacy of anti-cancer treatment. Accumulating evidence in non-neuronal cells shows that the copper transport system is associated with platinum drug sensitivity and resistance. There is minimal research concerning the role of copper transporters within the central and peripheral nervous systems. It is unclear whether neurons are more sensitive to platinum-based drugs, are insufficient in drug clearance, or whether platinum accumulation affects intracellular copper status and coppermediated functions. Understanding these mechanisms is important as neurotoxicity is the predominant side-effect of platinum-based chemotherapy. This review highlights the role of copper transpor ters in drug influx, differences in drug activation and side-effects caused by platinum-based agents, as well as their association with central and peripheral neuropathies and gastrointestinal toxicities.
authors.affiliation: College of Health and Biomedicine, Victoria University, Melbourne, Victoria. Australia.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Stojanovska
authors.affiliation: College of Health and Biomedicine, VCollege of Health and Biomedicine, Victoria University, Melbourne, Victoriaictoria University, Melbourne. Australia.
authors.forename: Rachel
authors.initials: R
authors.lastname: McQuade
authors.affiliation: College of Health and Biomedicine, VCollege of Health and Biomedicine, Victoria University, Melbourne, Victoriaictoria University, Melbourne. Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: Rybalka
authors.affiliation: Centre for Chronic Diseases, College of Health and Biomedicine, Victoria University, Western Centre for Health, Research and Education, 176 Furlong Road, St Albans, 3021, VIC. Australia.
authors.forename: Kulmira
authors.initials: K
authors.lastname: Nurgali
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D016190:Carboplatin / Q000627:therapeutic use / Q000633:toxicity; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002945:Cisplatin / Q000627:therapeutic use / Q000633:toxicity; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000627:therapeutic use / Q000633:toxicity; D000077150:Oxaliplatin; D010984:Platinum / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010984:Platinum; D016190:Carboplatin; D000251:Adenosine Triphosphatases; D002945:Cisplatin
keywords: Neurotoxicity; carboplatin; cisplatin; copper chaperones; copper transporters; oxaliplatin