Multidrug resistance (MDR) is one of the major therapeutic challenges that limits the efficacy of chemotherapeutic response resulting in poor prognosis of ovarian cancer (OC). The multidrug resistance protein 1 (MRP1) is a membrane-bound ABC transporter involved in cross resistance to many structurally and functionally diverse classes of anticancer drugs including doxorubicin, taxane, and platinum. In this study, we utilize homology modelling and molecular docking analysis to determine the binding affinity and the potential interaction sites of MRP1 with Carboplatin, Gemcitabine, Doxorubicin, Paclitaxel, and Topotecan. We used AutoDock Vina scores to compare the binding affinities of the anticancer drugs against MRP1. Our results depicted Carboplatin < Gemcitabine < Topotecan < Doxorubicin < Paclitaxel as the order of binding affinities. Paclitaxel has shown the highest binding affinity whereas Carboplatin displayed the lowest affinity to MRP1. Interestingly, our data showed that Carboplatin, Paclitaxel, and Topotecan bind specifically to Asn510 residue in the transmembrane domains 1 of the MRP1. Our results suggest that Carboplatin could be an appropriate therapeutic choice against MRP1 in OC as it couples weakly with Carboplatin. Further, our findings also recommend opting Carboplatin with Gemcitabine as a combinatorial chemotherapeutic approach to overcome MDR phenotype associated with recurrent OC.

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.

Despite advancements in therapeutics, early diagnosis of ovarian cancer (OC) remains a challenge due to its asymptomatic progression and it is often diagnosed at an advanced stage. Interleukin-8 (IL-8), a pro-inflammatory chemokine with angiogenic activity, plays a pivotal role in inflammation and carcinogenesis. Therefore, it is of interest to investigate the association between IL-8 polymorphisms and OC risk. A novel non-synonymous SNP (nsSNP, c.193G>A; p.Glu65Leu) was identified in exon 2 of the IL-8 gene in 5 patients, 3 with stage III and 2 with stage II tumor. Structural analysis suggested that the p.Glu65Leu mutation alters the IL 8 protein conformation showing functional impairment. Thus, data shows that IL-8 c.193 G>A (Glu65Leu) polymorphism may contribute to tumor susceptibility. However, further studies are warranted to understand the role of IL-8 polymorphism in OC.