Modulation of Multidrug resistance protein 1 (MRP1) activity as a strategy to chemosensitise and radiosensitise MRP1-expressing cancers

Abstract

Multidrug resistance is a leading contributor to treatment failure in cancer patients. As elevated levels of the antioxidant glutathione (GSH) and increased expression of drug efflux pumps may both contribute to chemotherapy resistance, depleting GSH and blocking drug efflux in cancer cells may improve response to treatment.

Multidrug resistance protein 1 (MRP1) is a membrane transporter that is frequently overexpressed in cancer cells. By actively effluxing a wide range of chemotherapeutic agents, MRP1 can protect the cancer cell from chemotherapy. GSH is also transported by MRP1 as a low-affinity endogenous substrate. Some small molecules (MRP1 'modulators'), upon binding to MRP1, greatly enhance this innate GSH transport whilst simultaneously blocking the efflux of chemotherapeutics. As this stimulated GSH efflux can deprive the cell of GSH, in parallel with the blocked chemotherapy efflux enhancing intracellular chemotherapy concentrations, MRP1 modulators might be used to exploit the high expression of MRP1 in cancer cells to improve treatment response.

MRP1 was found to be frequently expressed in patient tumours of two difficult to treat cancer types: non-small cell lung (NSCLC) and ovarian cancer. As this MRP1 expression might be leveraged with an MRP1 modulator, two modulators were tested on high MRP1-expressing NSCLC and ovarian cancer cell lines. As single agents, the modulators reduced MRP1 drug transport by >85% and improved the efficacy of MRP1-substrate chemotherapeutics (2 5-fold). In combination with the GSH synthesis inhibitor buthionine sulfoximine, complete GSH depletion, diminished clonogenic capacity, enhanced radiosensitivity, and extended chemosensitivity were achievable selectively in high MRP1-expressing cancer cells. As MRP1 expression in NSCLC was also associated with NRF2 activation, a key driver of treatment resistance in NSCLC, the modulator and buthionine sulfoximine combination was tested and found to be effective against cell lines representative of this highly resistant subset of NSCLC. Given the therapeutic potential for MRP1 modulators, their MRP1 binding site and mechanism of action as GSH transport modulators was investigated to provide a basis for future structure-guided design of more potent and selective modulators.

Overall, these findings support that the high expression of MRP1 in cancers can be exploited with MRP1 modulators to chemosensitise and radiosensitise NSCLC and ovarian cancers.