Pump resistance

One of the main mechanisms of MDR is pump resistance which is associated with membrane efflux pumps and reduced anticancer drug accumulation in cells (Nikolaou, Pavlopoulou, Georgakilas, & Kyrodimos, 2018). Multidrug efflux pumps are categorized into MDR associated-protein-1 (MRP1) and P-glycoprotein. P-glycoprotein is a member of superfamily ATP-dependent transporter that acts as an detoxifying agent and ejects toxin and xenobiotic by pumping positively or neutral charged chemotherapy medications out of the cells (e.g. vincristine, etoposide, doxorubicin (DOX) and actinomycin D) (Robey et al., 2018). MRP1 belongs to the ATP-binding cassette (ABC) transporter superfamily that can pump out various compounds instantiating anionic, hydrophobic, glutathione-conjugated (GSH) anticancer drugs and fluorescent dye (e.g. sulfate conjugates, folates, glucuronide conjugates, heavy metal anions and toxicants and etc.) (Nanayakkara et al., 2018). Various factors contribute to the occurrence of MDR in pancreatic cancer like blocking of apoptotic pathways, accelerated drug metabolism and DNA repair, reduced drug uptake, metabolic changes, and the presence of chemotherapy‐resistant cancer stem cells. ABC transporters play a central role in the reduction of intracellular accumulation of drugs and resulted pancreatic cancer MDR (Figure 4).
Figure 4. Schematic illustration of pump resistance and PLK1-mediated nom-pump resistance mechanism.