Colorectal cancer (CRC) is one of the most fatal types of
cancers that is seen in both men and women. CRC is the third most common type of
cancer worldwide. Over the years, several drugs are developed for the treatment of CRC; however, patients with advanced CRC can be resistant to some drugs.
P-glycoprotein (P-gp) (also known as Multidrug Resistance 1, MDR1) is a well-identified
membrane transporter protein expressed by ABCB1 gene. The high expression of
MDR1 protein found in several
cancer types causes
chemotherapy failure owing to efflux drug molecules out of the
cancer cell, decreases the drug concentration, and causes drug resistance. As same as other
cancers, drug-resistant CRC is one of the major obstacles for effective
therapy and novel therapeutic strategies are urgently needed. Network-based approaches can be used to determine specific
biomarkers, potential drug targets, or repurposing approved drugs in drug-resistant
cancers. Drug repositioning is the approach for using existing drugs for a new therapeutic purpose; it is a highly efficient and low-cost process. To improve current understanding of the MDR-1-related drug resistance in CRC, we explored gene co-expression networks around ABCB1 gene with different network sizes (50, 100, 150, 200 edges) and repurposed candidate drugs targeting the ABCB1 gene and its co-expression network by using drug repositioning approach for the treatment of CRC. The candidate drugs were also assessed by using molecular docking for determining the potential of physical interactions between the drug and
MDR1 protein as a drug target. We also evaluated these four networks whether they are diagnostic or prognostic features in CRC besides biological function determined by functional enrichment analysis. Lastly, differentially expressed genes of drug-resistant (i.e.,
oxaliplatin,
methotrexate, SN38) HT29 cell lines were found and used for repurposing drugs with reversal gene expressions. As a result, it is shown that all networks exhibited high diagnostic and prognostic performance besides the identification of various drug candidates for drug-resistant patients with CRC. All these results can shed light on the development of effective diagnosis, prognosis, and treatment strategies for drug resistance in CRC.