Retrospective evaluation of the clinical significance of multidrug resistance proteins in poor response to treatment of pc

Abstract

PC remains one of the most significant public health issues contributing to mortality in Sub-Sahara Africa, with South Africa being one of the most affected. Increased resistance to chemotherapy in PC patients is fast becoming a major concern and has led to increase investigation of its mechanisms. The present study investigated the expression of two genes, ABCB1 and CYP1B1, implicated in drug resistance in cancer cells. We also applied bioinformatics to unravel the molecular pathways and cascades linked to drug resistance that may be triggered following upregulation of these genes. Samples were collected from archived PC patient specimens obtained through pre-treatment biopsies. cDNAs synthesized from RNAs isolated from the samples, were subjected to qPCR analysis. qPCR analysis revealed a low expression of ABCB1, with concomitant high expression of CYP1B1 in PC cells. Gene enrichment and network analysis revealed ABCB1 to be associated with ABC transporters and LncRNA-mediated mechanisms of therapeutic resistance WP3672, while CYP1B1 is associated with ovarian steroidogenesis, tryptophan metabolism, steroid hormone biosynthesis, benzo(a)pyrene metabolism WP696, sulindac metabolic pathway WP2542 and estrogen receptor pathway WP2881. Both ABCB1 and CYP1B1 were associated with microRNAs in cancer and nuclear Receptors Meta-Pathway WP2882. STRING analysis further predicted a protein-protein interaction of ABCB1 and CYP1B1 with Glutathione S-transferase Pi; Catechol O-methyltransferase; UDP-glucuronosyltransferase 1-6; Leucine rich Transmembrane and O-methyltransferase (LRTOMT); and Epoxide hydrolase 1, and a score of 0.973, 0.971, 0.966, 0.966 and 0.966, respectively. Furthermore, molecular docking analysis of the regimen drug, docetaxel and CYP1B1 revealed a potent molecular interaction, with a binding energy of -20.37 Kcal/mol. These results indicate the susceptibility of the studied cancer patients to drug resistance via increased expression of ABCB1 and CYP1B1 in tumour samples of the poor responders’ category, and their associated molecular pathways. This is further depicted by the potent molecular interaction of CYP1B1 with docetaxel.