Intracellular drug sequestration events associated with the emergence of multidrug resistance: A mechanistic review

The acquisition of multi-drug resistance (MDR) in cancer cells subjected to anticancer agents remains a formidable obstacle to successful therapeutic outcomes in cancer patients. As the name implies, the resistance phenotype ( MDR) is not typically limited to the drug initially used to eradicate cancer but is often transferred to structurally unrelated chemotherapeutic agents. The mechanisms underlying the development of MDR have been extensively studied and are considered multifactorial. Interestingly, recent observations have shown that altered intracellular distribution of drugs may play an important role in the establishment of the MDR phenotype. Such intracellular redistribution events may reduce the opportunity for a drug molecule to permeate into a drug target-containing compartment and thus limit its therapeutic effect. This review summarizes cases in which intracellular redistribution of drugs has been associated with the emergence of MDR in cancer cells. The review also provides a general overview regarding intracellular compartmentalization mechanisms of drugs in cells, which will include some of the known factors/conditions that influence the accumulation of drugs into specific cellular compartments. Finally, potential strategies for overcoming this resistance phenotype are discussed.