Is glutathione the major cellular target of cisplatin? A study of the interactions of cisplatin with cancer cell extracts

Yonit Kasherman, Stefan Sturup, Dan Gibson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

128 Scopus citations

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 [1H,15N] HSQC that the half-life of 15N labeled cisplatin in whole cell extracts is ∼75 min, but no Pt-GSH adducts were observed. When the low molecular mass fraction (<3 kDa) of the extracts was incubated with cisplatin, binding toGSHwas observed probably due to removal of high molecular mass platinophiles. Two-thirds of the Pt adducts formed in whole cell extracts, had a molecular mass > 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.

Original languageEnglish
Pages (from-to)4319-4328
Number of pages10
JournalJournal of Medicinal Chemistry
Volume52
Issue number14
DOIs
StatePublished - 23 Jul 2009

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