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

Yonit Kasherman; Stefan Stürup; dan gibson

doi:10.1021/jm900138u

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

Yonit Kasherman, Stefan Stürup, dan gibson

91 Citations (Scopus)

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 to GSH was 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 language	English
Journal	Journal of Medicinal Chemistry
Volume	52
Issue number	14
Pages (from-to)	4319-4328
Number of pages	10
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm900138u
Publication status	Published - 18 Jun 2009

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title = "Is Glutathione the Major Cellular Target of Cisplatin?: A Study of the Interactions of Cisplatin with Cancer Cell Extracts",

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 to GSH was 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.",

author = "Yonit Kasherman and Stefan St{\"u}rup and dan gibson",

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doi = "10.1021/jm900138u",

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TY - JOUR

T1 - Is Glutathione the Major Cellular Target of Cisplatin?

T2 - A Study of the Interactions of Cisplatin with Cancer Cell Extracts

AU - Kasherman, Yonit

AU - Stürup, Stefan

AU - gibson, dan

PY - 2009/6/18

Y1 - 2009/6/18

N2 - 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 to GSH was 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.

AB - 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 to GSH was 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.

U2 - 10.1021/jm900138u

DO - 10.1021/jm900138u

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C2 - 19537717

SN - 0022-2623

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SP - 4319

EP - 4328

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 14

ER -

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

Abstract

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