Evaluation of potential substrates and inhibitors of MRP2 transporter to predict effective combinatorial chemotherapeutic agents for treating MRP2-associated non-responsive colorectal cancer

Colorectal cancer (CRC) is a significant cause of death globally, due to the emergence of multidrug resistance (MDR), which limits the effectiveness of conventional chemotherapy. Multidrug resistance-associated protein 2 (MRP2) plays a critical role in the drug resistance observed in cancer. MRP2 contributes to cross-resistance to several structurally and functionally diverse chemotherapeutic drugs. This study aims to evaluate potential anticancer agents and inhibitors of MRP2 to develop effective therapeutic strategies for MRP2-associated non-responsive CRC. In this study, molecular docking was performed to reveal the MRP2 binding sites and affinity with anticancer drugs. Interaction analysis of chemotherapeutic drugs with MRP2 demonstrated irinotecan>doxorubicin>capecitabine>trifluridine>oxaliplatin>gemcitabine>tipiracil>5-Fluorouracil (5-FU) to be the decreasing order of binding affinities. 5-FU exhibited the lowest binding affinity, while irinotecan displayed the highest. In contrast, docking analysis of inhibitors with MRP2 showed probencid<MK-571<S-(2,4-dinitrophenyl) glutathione<dihydromyricetin <zafirlukast< montelukast to be the order of increasing binding affinities. Montelukast showed the highest binding affinity with MRP2. Notably, our findings showed that irinotecan, oxaliplatin, montelukast, and zafirlukast bind specifically to MRP2 regions TM12 and TM15. Our results suggest that 5-FU could be a more effective option for MRP2-overexpressing CRC as it interacts poorly with MRP2. Additionally, gemcitabine and oxaliplatin shared common binding sites, implying that competitive binding may help overcome MDR. Furthermore, our findings imply that a combinatorial approach utilizing irinotecan/oxaliplatin and an inhibitor may offer an efficient approach to combat drug resistance in CRC, paving the way for improved patient outcomes.