Abstract

Abstract Multidrug resistance protein 1 (MRP1) is frequently overexpressed in tumors where it effluxes chemotherapeutic agents, protecting tumor cells from chemotherapy. This is clearly illustrated in the pediatric solid tumor neuroblastoma, where MRP1 expression is highly prognostic of clinical outcome (1,2) and contributes to chemoresistance in mouse models (3). MRP1 also effluxes low levels of glutathione (GSH), a crucial intracellular antioxidant necessary to avoid damage from the reactive oxygen species induced by radiotherapy and chemotherapy and an important component of both Phase II and Phase III drug metabolism. Depletion of GSH in cancer cells would be of therapeutic value, however the GSH synthesis inhibitor L-buthionine sulfoximine (BSO) has only limited selectivity for tumor over normal cells. We have identified a novel MRP1 inhibitor, 7-methyl-5-phenyl-2-[(4-phenyl-1-piperazinyl)carbonyl]pyrazolo[1,5-a]pyrimidine, that blocks MRP1-mediated drug efflux while greatly enhancing MRP1- mediated GSH efflux and are investigating the utility of this dual-function inhibitor for the treatment of MRP1-overexpressing cancers. Methods: Cells expressing high levels of MRP1 were treated with MRP1 drug substrates in combination with MRP1 inhibitors. Viability was assessed by short-term cytotoxicity or clonogenic assays and GSH levels determined by glutathione recycling assay. Results: Our MRP1 modulator depleted intracellular GSH in an MRP1-dependent manner and sensitized MRP1-expressing human neuroblastoma, lung and ovarian cancer cell to chemotherapeutics. This effect was highly synergistic with BSO, both in depleting GSH (CI<0.36, p<0.05) and abolishing colony formation (CI<0.01, p<0.05). Conclusion: Our MRP1 modulator blocks MRP1- mediated drug efflux while greatly enhancing MRP1- mediated GSH efflux in MRP1 expressing cells, potentially providing an increased therapeutic window for chemotherapeutics in MRP1- overexpressing cancers. Synergy with BSO could widen the range of drugs and cancers that this could be beneficial for.

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