Table 1: Summary of mechanisms of MDR [5, 6].

Mechanism of MDRDescription

Uptake transport of drugDecreased expression of uptake transporters (reduced-folate transporters) and alternation in lipid metabolism modifying biophysical properties of the lipid bilayer influence drug uptake

Activation of detoxifying enzymesInactivation of drug by phase I and phase II enzymes

Drug sequestrationDrug can be trapped in subcellular organelles such as lysosomes and endosomes and then extruded from the cell

Avoiding to drug induced apoptosisOccurs mostly via mitochondrial pathway; disruption of balance between pro-/antiapoptotic factors leads to survival of cancer cells

Enhanced DNA reparationCells with damaged DNA avoid to senescence, apoptosis, or necrosis

Overexpression of membrane transportersEnhanced drug efflux by ABC transporters

Alternation in target moleculesDNA metylation, mutation of topoisomerases I and II

MicroenvironmentPh, hypoxia, population of quiescent cells

Altered signaling pathwaysBlock of apoptosis and expression of genes involved in DNA reparation and efflux pump