Is Glutathione the Major Cellular Target of Cisplatin? A Study of the Interactions of Cisplatin with Cancer Cell Extracts

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Abstract

Cisplatin is an anticancer drug whose efficacy is limited because tumors develop resistance to the drug. Resistant cells often have elevated levels of cellular glutathione (GSH), believed to be the major cellular target of cisplatin that inactivates the drug by binding to it irreversibly, forming [Pt(SG)(2)] adducts. We show by [(1)H,(15)N] HSQC that the half-life of (15)N labeled cisplatin in whole cell extracts is approximately 75 min, but no Pt-GSH adducts were observed. When the low molecular mass fraction (3 kDa. [Pt(SG)(2)] cannot account for more than 20% of the Pt adducts. The concentration of reduced thiols in the high molecular mass fraction of the extracts is six times higher than in the low molecular mass fraction.

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