The Emergence of Drug Transporter-Mediated Multidrug Resistance to Cancer Chemotherapy

Abstract

Chemotherapy is currently one of the most effective ways to treat metastatic cancers. However, of the various mechanisms that are involved in conferring resistance, upregulation of drug efflux ATP-binding cassette (ABC) transporters, such as P-glycoprotein (ABCB1), multidrug resistance protein 1 (ABCC1) and ABCG2, has become a major obstacle to cancer chemotherapy and seriously affects the clinical outcome. To date, at least 15 ABC drug transporters have been identified and characterized to transport and confer resistance to practically the entire spectrum of cancer drugs, causing multidrug resistance (MDR) in cancers. Unfortunately, despite decades of research, there is still no real solution to MDR. This review highlights some of the major findings, the roles and problems associated with MDR-linked ABC drug transporters in metastatic cancers and solid tumors, and the current strategies to improve the clinical outcome in cancer chemotherapy.

NF-κB signaling plays irreplaceable roles in cisplatin-induced bladder cancer chemoresistance and tumor progression

“…ABC transporters 'pump' drugs, such as anti-neoplastic drugs, out of the cells against a concentration gradient, this is the basic mechanism of chemoresistance (10). To date, 48 members of the ABC transporter family have been isolated and identified (11,12).…”

Anticancer Drug Metabolism: Chemotherapy Resistance and New Therapeutic Approaches

“…For example, drug efflux transporters including the P-glycoprotein pump (Pgp), the multidrug-resistant protein-1 (MRP1) and the BCRP actively pump drugs such as chemotherapeutics out of the cells, thereby reducing their intracellular accumulation and making the cell insensitive to different drugs such as anthracyclines, vinca-alkaloids or taxanes. Among the major known ABC transporters, ABCB1 gene, also known as MDR1, encoding Pgp is by far the best characterized and understood efflux transporter (Goda et al, 2009;Wu et al, 2011). It is predominantly expressed in several tissues including the luminal surface of intestinal epithelia, the renal proximal tubule, the bile canalicular membrane of hepatocytes and the blood brain barrier (Ho and Kim, 2005).…”

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“…[1][2][3][4][5][6][7] Nearly 90% of tumor cells gradually become insensitive and MDR occurs after repeated exposure of drugs to the tumor cells for a certain time. 8,9 Tumor cells can survive after exposure to chemotherapy drugs to produce MDR through inhibition of apoptosis and other ways. [10][11][12][13][14] Although the mechanism of MDR is complicated, it is well known that transmembrane transporters such as proteins, including permeability glycoprotein (P-glycoprotein [P-gp]), MDR-associated protein (MRP), lung resistanceassociated protein (LRP), and breast cancer-resistant protein (BCRP), transport drugs out of cell plasma across the membrane of cancer cells.…”