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 γ-glutamylcysteine synthesis (γ-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 γ-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.
Highlights
Cisplatin (CDDP) has been the mainstay for the treatment of a broad spectrum of human malignancies since it was approved by the FDA about 30 years ago
In 1998, while we were studying the coregulation of γGCSh and MRP1 by CDDP, we found that transfection of recombinant DNA encoding the γ-GCSh subunit alone was sufficient to enhance GSH levels in the transfected cells [29]
We investigated the regulation of hCtr1 expression in response to Cu concentration stress and found that levels of hCtr1 mRNA were decreased in cultured small cell lung cancer (SCLC) cells treated with CuSO4 but were increased in cells treated with the Cu-depleting agent bathocuproine disulfonic acid
Summary
Cisplatin (CDDP) has been the mainstay for the treatment of a broad spectrum of human malignancies since it was approved by the FDA about 30 years ago. It has been used in the first-line treatment modalities of human malignancies, including testicular [1], ovarian [2, 3], cervical [4], bladder [5], head and neck [6], and small cell lung cancers (SCLCs) [3, 7, 8]. It is conceivable that multiple mechanisms are involved in CDDP resistance, including reduction of drug transport and increased DNA adduct tolerance and repair [9, 10]. The first mechanism involves the effects of GSH on the ATP-binding cassette (ABC) transportermediated CDDP transport; the second mechanism involves the redox-regulating capacity of GSH in detoxifying CDDP toxicity; the third mechanism involves regulation of the intracellular copper pool that affects CDDP uptake
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