Background: Resistance to chemotherapy is often the cause of treatment failure and death of cancer patients. Multidrug resistance protein 1 (MRP1) reduces drug efficacy and negatively affects patient outcome by actively pumping a range of conventional chemotherapeutic agents out of cancer cells, often in co-transport with glutathione (GSH) (1,2). As MRP1-expressing cancer cells are hypersensitive to GSH depletion (3), we investigated an MRP1 modulator that enhances MRP1-mediated GSH efflux while blocking drug efflux. We hypothesised that this modulator would be highly effective in depleting GSH and sensitising high MRP1-expressing cancers to chemotherapy and radiotherapy.
Methods: The ability of our modulator to inhibit drug transport by MRP1; chemosensitise MRP1-expressing neuroblastoma, lung cancer, and ovarian cancer cell lines; and synergise with the GSH synthesis inhibitor BSO to deplete GSH and radiosensitise was measured by radiolabel uptake, cytotoxicity, and clonogenic assays respectively. GSH levels were determined by glutathione recycling assay. MRP1 expression in neuroblastoma, lung cancer, and ovarian cancer patient samples was assessed by IHC.
Results/Conclusions: Our MRP1 modulator potently inhibited drug transport with a lower IC50 than Reversan, a commerically available MRP1 inhibitor. Our MRP1 modulator increased the efficacy of multiple chemotherapeutic agents by 2-6-fold in high MRP1-expressing cancer cells. Striking synergy was observed between the MRP1 modulator and BSO, driving near complete GSH depletion, diminishing clonogenic capacity, improving chemosensitisation, and radiosensitising MRP1-expressing cells. Notably, these effects were selective for high MRP1-expressing cells. As MRP1 was frequently expressed in the lung and ovarian cancer cohorts, MRP1 modulators may be a strategy to allow lower doses of chemotherapy to be used to greater effect and expand the therapeutic window available to treat resistant, MRP1-overexpressing tumours.