Relevance of multidrug resistance in the age of targeted therapy.
Targeted drugs inhibit specific pathways that contribute to the malignant phenotype of cancer cells. The initial success of molecularly targeted therapies raised hope that newly developed agents would evade the general mechanisms of resistance that have reduced the efficacy of traditional anticancer drugs. In recent years, ATP-binding cassette (ABC) transporters related to multidrug resistance (MDR), such as P-glycoprotein (P-gp; ABCB1/MDR1) and ABCG2 (breast cancer resistance protein/mitoxantrone resistance protein) have emerged as key factors that regulate the intracellular concentrations of many small-molecule therapeutic inhibitors. Drug transporters may be overexpressed in cancer cells, reducing intracellular drug concentrations, and may allow the evolution of point mutations that confer stronger drug resistance. It is proposed that P-gp, a universally accepted biomarker of drug resistance, should also be considered as a molecular target in multidrug-resistant cancer. By exploiting the paradoxical hypersensitivity of multidrug-resistant cells, MDR1-inverse compounds can selectively eliminate cancer cells that overexpress P-gp. Successful targeting of multidrug-resistant cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors.
Türk
Dóra
D
Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, 1113 Budapest, Karolina u. 29, Hungary.
Szakács
Gergely
G