GlutathioneS-Transferase M1 and Multidrug Resistance Protein 1 Act in Synergy to Protect Melanoma Cells from Vincristine Effects

Abstract

Previous studies have shown that glutathione S-transferases (GSTs) can operate in synergy with efflux transporters, multidrug resistance proteins (MRPs), to confer resistance to several carcinogens, mutagens and anticancer drugs. To address the poorly documented role of the GSTM1 in cancer chemoresistance, we used CAL1 human melanoma cells expressing no endogenous GSTM1 and a high level of MRP1. Cells were transfected with an expression vector containing the GSTM1 cDNA, and different clones were selected expressing different levels of GSTM1 (RT-PCR, Western blot, and enzyme activity). Cells overexpressing GSTM1 displayed a 3-to 4-fold increase in resistance to anticancer drugs vincristine (VCR) and chlorambucil (CHB) in proliferation, cytotoxic, and clonogenic survival assays. Inhibitors of MRP1 (sulfinpyrazone, verapamil) and GST (dicumarol, curcumin) completely reversed the GSTM1-associated resistance to VCR, indicating that a MRP efflux function is necessary to potentiate GSTM1-mediated resistance to VCR. Conversely, MRP1 inhibitors had no effect on the sensitivity to CHB. Using immunofluorescence assay, GSTM1 was also shown to protect microtubule network integrity from VCR-induced inhibition of microtubule polymerization. In conclusion, these results show that GSTM1 alone is involved in melanoma resistance to CHB, whereas it can act in synergy with MRP1 to protect cells from toxic effects of VCR.

Relation Between Animal-Type Melanoma and Reduced Nuclear Expression of Glutathione S-Transferase π

“…25,26 Glutathione S-transferases operate in synergy with specific proteins to confer a multidrug resistance to the melanoma and nonmelanoma tumor cells. 27,28 The GST-isoform is likely to make adducts with anticancer drugs and facilitate their transport outside the cells 29,30 ; GST-nuclear amount does not depend on the cytoplasmic level. 31 Low nuclear GST-expression seems to confirm indirectly that ATM is a morphologically distinct entity that can be distinguished from conventional melanomas.…”

Defining regional infusion treatment strategies for extremity melanoma: comparative analysis of melphalan and temozolomide as regional chemotherapeutic agents

“…One study suggested that increased expression of GSTA1 is primarily responsible for acquired drug resistance (30), whereas other studies have suggested that GSTP1 and GSTM1 are responsible for drug resistance (32,33). Horton et al (34) showed a near-linear correlation between resistance to a bifunctional alkylating agent and overexpression of the A class of GSTs and suggested that overexpression of the GSTMs may be responsible for the observed resistance of ovarian carcinoma cells to bifunctional alkylating agents.…”

Inhibition of glutathione-S-transferase as a treatment strategy for multidrug resistance in childhood rhabdomyosarcoma

“…GSTs might mediate the development of MDR via direct detoxification and as an inhibitor of the MAP kinase pathway. Up-regulation of GSTs has been reported in several cancer types (12) including melanoma cells which were resistant to vincristine (13). Moreover, a reversal of these effects was also seen after the usage of GST inhibitors like dicumarol or curcumin (13).…”

“…Up-regulation of GSTs has been reported in several cancer types (12) including melanoma cells which were resistant to vincristine (13). Moreover, a reversal of these effects was also seen after the usage of GST inhibitors like dicumarol or curcumin (13). Therefore, a broad range of GST inhibitors were developed to modulate drug resistance and to sensitize tumor cells to cytotoxic drugs (11,14).…”