Revisiting the ABCs of Multidrug Resistance in Cancer Chemotherapy

Amit      K. Tiwari; Kamlesh      Sodani; Chun-Ling      Dai; Charles      R. Ashby; Zhe-Sheng      Chen

doi:10.2174/138920111795164048

Abstract

The adenosine triphosphate binding cassette (ABC) transporters are one of the largest transmembrane gene families in humans. The ABC transporters are present in a number of tissues, providing protection against xenobiotics and certain endogenous molecules. Unfortunately, their presence produces suboptimal chemotherapeutic outcomes in cancer patient tumor cells. It is well established that they actively efflux antineoplastic agents from cancer cells, producing the multidrug resistance (MDR) phenotype. The inadequate response to chemotherapy and subsequent poor prognosis in cancer patients can be in part the result of the overexpression of ABC transporters. In fact, one of the targeted approaches for overcoming MDR in cancer cells is that directed towards blocking or inhibiting ABC transporters. Indeed, for almost three decades, research has been conducted to overcome MDR through pharmacological inhibition of ABC transporters with limited clinical success. Therefore, contemporary strategies to identify or to synthesize selective “resensitizers” of ABC transporters with limited nonspecific toxicity have been undertaken. Innovative approaches en route to understanding specific biochemical roles of ABC transporters in MDR and tumorigenesis will prove essential to direct our knowledge towards more effective targeted therapies. This review briefly discusses the current knowledge regarding the clinical involvement of ABC transporters in MDR to antineoplastic drugs and highlights approaches undertaken so far to overcome ABC transporter-mediated MDR in cancer.

Keywords: ABC transporters, cancer chemotherapy, chemosensitizers, MDR modulators, multidrug resistance, P-glycoprotein, tyrosine kinase inhibitors, xenobiotics, efflux antineoplastic agents, multidrug resistance (MDR) phenotype, overexpression, resensitizers, targeted therapies, consensus sequence, identical functional unit sequences