Chemical basis for the detoxification of cisplatin-derived hydrolysis products by sodium thiosulfate.
Cisplatin remains the most widely used platinum-based anti-cancer drug and is included on the World Health Organization's list of essential medicines. Cisplatin also exhibits severe toxic side-effects, in particular damage to both the kidney and the inner ear, which are thought to derive primarily from hydrolysis products that are more toxic than cisplatin itself. Selective inactivation of these hydrolysis products has emerged as a feasible strategy to mitigate side effects and transform cisplatin into a better medicinal drug. Sodium thiosulfate is one of the most promising of currently considered mitigation agents, and co-administration of large quantities with cisplatin has been shown to considerably reduce toxic side effects in animals without abolishing useful anti-cancer cytotoxicity. The structural basis of this antagonism has, however, remained uncertain. We report herein the structural characterization of the reaction product of hydrolyzed cisplatin and thiosulfate in aqueous solution using X-ray absorption spectroscopy. This reveals the formation of the four-coordinate Pt(II) species [Pt(S2O3)4]6-with Pt-S bond lengths of 2.30Å. Our structural conclusions are supported by density functional theory calculations. More generally speaking, the structural characterization of this Pt-thiosulfate complex reinvigorates the principle strategy to reduce the toxicity of cisplatin (and possibly other platinum-based anticancer drugs) by co-administering appropriate ameliorating agents for direct benefits to patients.
Department of Chemistry, University of Calgary, Calgary, AB T2N 1N4, Canada.
Melani
M
Sooriyaarachchi
Department of Chemistry, University of Calgary, Calgary, AB T2N 1N4, Canada. Electronic address: j.gailer@ucalgary.ca.
Jürgen
J
Gailer
Molecular and Environmental Science Research Group, Department of Geological Sciences, University of Saskatchewan, Saskatoon, SK S7N 5E2, Canada.
Natalia V
NV
Dolgova
Molecular and Environmental Science Research Group, Department of Geological Sciences, University of Saskatchewan, Saskatoon, SK S7N 5E2, Canada; Toxicology Center, University of Saskatchewan, Saskatoon, SK S7N 5B3, Canada; Department of Chemistry, University of Saskatchewan, Saskatoon, SK S7N 5C9, Canada.
Ingrid J
IJ
Pickering
Molecular and Environmental Science Research Group, Department of Geological Sciences, University of Saskatchewan, Saskatoon, SK S7N 5E2, Canada; Toxicology Center, University of Saskatchewan, Saskatoon, SK S7N 5B3, Canada; Department of Chemistry, University of Saskatchewan, Saskatoon, SK S7N 5C9, Canada. Electronic address: g.george@usask.ca.
Graham N
GN
George
D000970:Antineoplastic Agents / Q000737:chemistry*; D002945:Cisplatin / Q000737:chemistry*; D056831:Coordination Complexes / Q000737:chemistry*; D006868:Hydrolysis; D008658:Inactivation, Metabolic; D008968:Molecular Conformation; D011789:Quantum Theory; D012996:Solutions; D013816:Thermodynamics; D013885:Thiosulfates / Q000737:chemistry*; D014867:Water / Q000737:chemistry; D056928:X-Ray Absorption Spectroscopy
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D012996:Solutions; D013885:Thiosulfates; D014867:Water; C017717:sodium thiosulfate; D002945:Cisplatin
Ameliorating agent; Cisplatin; DFT; EXAFS; Thiosulfate; XAS