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.