Role of glutathione in the regulation of cisplatin resistance in cancer chemotherapy

MacUs Tien Kuo, Helen H.W. Chen

Research output: Contribution to journalReview article

108 Citations (Scopus)

Abstract

Three mechanisms have been proposed for the role of glutathione (GSH) in regulating cisplatin (CDDP) sensitivities that affects its ultimate cell-killing ability: (i) GSH may serve as a cofactor in facilitating multidrug resistance protein 2- (MRP2-) mediated CDDP efflux in mammalian cells, since MRP2-transfected cells were shown to confer CDDP resistance; (ii) GSH may serve as a redox-regulating cytoprotector based on the observations that many CDDP-resistant cells overexpress GSH and -glutamylcysteine synthesis ( -GCS), the rate-limiting enzyme for GSH biosynthesis; (iii) GSH may function as a copper (Cu) chelator. Elevated GSH expression depletes the cellular bioavailable Cu pool, resulting in upregulation of the high-affinity Cu transporter (hCtr1) which is also a CDDP transporter. This has been demonstrated that overexpression of GSH by transfection with -GCS conferred sensitization to CDDP toxicity. This review describes how these three models were developed and critically reviews their importance to overall CDDP cytotoxicity in cancer cell treatments.

Original languageEnglish
Article number430939
JournalMetal-Based Drugs
Volume2010
DOIs
Publication statusPublished - 2010 Oct 20

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Chemotherapy
Cisplatin
Glutathione
Cells
Drug Therapy
Biosynthesis
Cytotoxicity
Chelating Agents
Toxicity
Copper
Neoplasms
Enzymes
Oxidation-Reduction
Transfection
Up-Regulation
P-glycoprotein 2

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Pharmacology
  • Drug Discovery
  • Inorganic Chemistry

Cite this

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Role of glutathione in the regulation of cisplatin resistance in cancer chemotherapy. / Kuo, MacUs Tien; Chen, Helen H.W.

In: Metal-Based Drugs, Vol. 2010, 430939, 20.10.2010.

Research output: Contribution to journalReview article

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AB - Three mechanisms have been proposed for the role of glutathione (GSH) in regulating cisplatin (CDDP) sensitivities that affects its ultimate cell-killing ability: (i) GSH may serve as a cofactor in facilitating multidrug resistance protein 2- (MRP2-) mediated CDDP efflux in mammalian cells, since MRP2-transfected cells were shown to confer CDDP resistance; (ii) GSH may serve as a redox-regulating cytoprotector based on the observations that many CDDP-resistant cells overexpress GSH and -glutamylcysteine synthesis ( -GCS), the rate-limiting enzyme for GSH biosynthesis; (iii) GSH may function as a copper (Cu) chelator. Elevated GSH expression depletes the cellular bioavailable Cu pool, resulting in upregulation of the high-affinity Cu transporter (hCtr1) which is also a CDDP transporter. This has been demonstrated that overexpression of GSH by transfection with -GCS conferred sensitization to CDDP toxicity. This review describes how these three models were developed and critically reviews their importance to overall CDDP cytotoxicity in cancer cell treatments.

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