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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	52
Udgave nummer	14
Sider (fra-til)	4319-4328
Antal sider	10
ISSN	0022-2623
DOI	https://doi.org/10.1021/jm900138u
Status	Udgivet - 18 jun. 2009

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10.1021/jm900138u

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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",

year = "2009",

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doi = "10.1021/jm900138u",

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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

M3 - Journal article

C2 - 19537717

SN - 0022-2623

VL - 52

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

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