Multidrug resistance (MDR) in cancer cells is a phenotype whereby cells display reduced sensitivity to anticancer drugs, based on a variety of mechanisms, including an increase in drug efflux, the reduction of drug uptake, the activation of cell growth and survival signaling, the promotion of DNA repair, and the inhibition of apoptosis signaling. Increased expression of the plasma membrane drug efflux pumps, the ATP-binding cassette (ABC) transporters, is involved in MDR. P-Glycoprotein/ABCB1 is a member of the ABC transporter family, and facilitates the efflux of various anticancer drugs, including anthracyclines, vinca alkaloids, epipodophyllotoxins, taxanes, and kinase inhibitors, from cells. P-Glycoprotein is also expressed in normal tissues and cells, including the kidney, liver, colon, and adrenal gland, to transport and/or secrete substrates and at the blood-brain, blood-placenta, and blood-testis barriers to protect these tissues from toxic substances. To understand the mechanistic functions of P-glycoprotein and to overcome MDR, investigators have identified the substrates and competitive inhibitors of P-glycoprotein. Recently, we and other groups reported associations between cellular signaling pathways and the expression, stability, degradation, localization, and activity of P-glycoprotein. The present review summarizes the currently available information about the transcriptional and posttranslational regulation of P-glycoprotein expression and function. 1. Molecular Characterization of P-Glycoprotein in Cancer Resistance to a broad spectrum of chemotherapeutic agents in cancer is called “multidrug resistance” (MDR) and is a major problem in chemotherapy. MDR often appears during cancer chemotherapy or during recurrence after chemotherapy [1]. It is caused by various mechanisms, including an increase in drug efflux, the reduction of drug uptake, the activation of growth signaling and DNA repair pathways, and the inhibition of the apoptosis signaling pathway by the induction of antiapoptotic molecules [2]. The ATP-binding cassette (ABC) transporters are key molecules in the drug uptake and efflux [3]. They are characterized by transmembrane domains (TMDs) and nucleotide-binding domains (NBDs) with the Walker A, Walker B, and Signature C motifs [3]. The human ABC transporters consist of 48 or 49 family members [3]. Among these, P-glycoprotein (ABCB1), breast cancer resistance protein (BCRP/MXR/ABC-P/ABCG2), and multidrug resistance-associated proteins (MRP1/ABCC1 and MRP2/ABCC2) function as drug efflux pumps of anticancer drugs, and their
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