Revisiting the ABCs of Multidrug Resistance in Cancer Chemotherapy

Abstract

The adenosine tri-phosphate 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 clinical 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 role 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.

The Interaction Between Redox and Hypoxic Signalling Pathways in the Dynamic Oxygen Environment of Cancer Cells

“…These proteins use ATP to transport drugs out of cells [109]. One highly studied ABC transporter protein is P-glycoprotein (Pgp) (an MDR1 gene product) that has been linked to MDR in cancer cells [110]. High levels of Pgp are found in MDR cells and coincide with higher expression of HIF-1 [111][112][113].…”

Doxorubicin and 5-fluorouracil resistant hepatic cancer cells demonstrate stem-like properties

“…In addition, overexpression of the ABC transporter is usually related to stem cell markers such as CD133, nestin, CD117 (Adhikari et al 2010), Notch-1 and Nanog (Patrawala et al 2005;Bourguignon et al 2008) as well as Oct-4 . Inhibition of ABC transporters reduces the multidrug resistance of some cancer types Peng et al 2010;Moitra et al 2011;Tiwari et al 2011;Meyer zu Schwabedissen and Kroemer 2011). Therefore, a side population (SP) by exclusion of Hoechst 33342 dye was used to isolate HCSC population (Chiba et al 2006).…”

Pharmacogenomics Dictate Pharmacokinetics: Polymorphisms in Drug-Metabolizing Enzymes and Drug-Transporters

“…The overexpression of ABC transporters had been shown to result in chemotherapeutics being pumped out of cells faster than they can enter, and is an well accepted mechanism leading to the development of multidrug resistance (MDR) in cancer cells (Gottesman MM, 2002;Luqmani YA. 2005;Tiwari AK, 2011). Recent studies by us, and others, have also shown that several anti-HIV-1 drugs, especially HIV protease inhibitors (HPIs) and nucleoside analog reverse transcriptase inhibitors (NRTIs) are substrates of ABC-transporters (Choo EF, 2000;Roy U, 2009) and their expression on both lymphocytes and BBB endothelial cells (ECs) can suppress drug entry into the cellular and anatomical reservoirs of HIV-1 (Eilers M, 2008;Tarbell JM.…”