Molecular Pathways: Regulation and Therapeutic Implications of Multidrug Resistance

Abstract

Multidrug transporters constitute major mechanisms of multidrug resistance (MDR) in human cancers. The ABCB1 (MDR1) gene encodes a well-characterized transmembrane transporter, termed P-glycoprotein (P-gp), which is expressed in many normal human tissues and cancers. P-gp plays a major role in the distribution and excretion of drugs, and is involved in intrinsic and acquired drug resistance of cancers. The regulation of ABCB1 expression is complex, and has not been well studied in a clinical setting. In this review, we elucidate molecular signaling and epigenetic interactions that govern ABCB1 expression and the development of MDR in cancer. We focus on acquired expression of ABCB1 that is associated with genomic instability of cancer cells, including mutational events that alter chromatin structures, gene rearrangements, and mutations in tumor suppressor proteins (e.g., mutant p53) that guard the integrity of genome. In addition, epigenetic modifications of the ABCB1 proximal and far upstream promoters by either demethylation of DNA or acetylation of histone H3 play a pivotal role in inducing ABCB1 expression. We describe a molecular network that coordinates genetic and epigenetic events leading to the activation of ABCB1. These mechanistic insignts provide additional translational targets and potential strategies to deal with clinical MDR.

Rewired Metabolism in Drug-resistant Leukemia Cells

“…Consequently, under therapeutic pressure, following the principles of natural selection, cancer cell populations that are most adaptive or resistant to treatment will be selected for, resulting in relapsing disease often associated with a worse prognosis (1,4,5). Relapse is commonly accompanied by overexpression of the ATP-binding cassette transporter ABCB1 gene product, P-glycoprotein (P-gp) 3 (multidrug resistance protein 1) (6), a drug efflux pump that is a marker for both tumor resistance to chemotherapy and a more aggressive phenotype (7)(8)(9). However, P-gp inhibition has been unsuccessful in clinical trials (7,8) so it is imperative to identify other targetable molecular mechanisms that are essential for cells with a drug-resistant phenotype to improve the prognosis of relapsing leukemia.…”

“…Relapse is commonly accompanied by overexpression of the ATP-binding cassette transporter ABCB1 gene product, P-glycoprotein (P-gp) 3 (multidrug resistance protein 1) (6), a drug efflux pump that is a marker for both tumor resistance to chemotherapy and a more aggressive phenotype (7)(8)(9). However, P-gp inhibition has been unsuccessful in clinical trials (7,8) so it is imperative to identify other targetable molecular mechanisms that are essential for cells with a drug-resistant phenotype to improve the prognosis of relapsing leukemia.…”

MDR-1, Bcl-xL, H. pylori, and Wnt/β-catenin signalling in the adult stomach: how much is too much?

“…The membrane transporter P-glycoprotein (MDR-1, Pgp) encoded by the adenosine triphosphate-binding cassette, subfamily B, member 1 is the main mechanism for decreased intracellular drug accumulation in MDR cancer. 1 Increases in Mdr-1 expression prevent tumor cells from a variety of induced apoptosis, but how this occurs is poorly understood. It is essential to understand how this occurs to be able to design effective therapeutic interventions.…”

Cytotoxic Effects and Multidrug Resistance Modulation by Five Benzophenones and a Xanthone Isolated fromHypericum AnnulatumMoris SUBSP.Annulatum

“…hence, MDR is a phenomenon, whereby cancer cells exposed to one anticancer drug acquire resistance to various agents that are both chemically and pharmacologically distinct from the initially utilized medicine (15,50,52,56). Although there are several alternative mechanisms implicated in MDR (11,15,43), this phenomenon is typically associated with overexpression of the AtP-binding cassette (ABc) family of membrane transporters, capable of pumping anticancer drugs out of cells, thus lowering their availability at the intracellular target-sites to levels devoid of cytotoxic activity (13,15,51). The prototypical efflux transporter, implicated in MDR is P-glycoprotein (P-gp) (13).…”

“…Although there are several alternative mechanisms implicated in MDR (11,15,43), this phenomenon is typically associated with overexpression of the AtP-binding cassette (ABc) family of membrane transporters, capable of pumping anticancer drugs out of cells, thus lowering their availability at the intracellular target-sites to levels devoid of cytotoxic activity (13,15,51). The prototypical efflux transporter, implicated in MDR is P-glycoprotein (P-gp) (13). This efflux pump is responsible for the unilateral, ATP-dependent efflux of various xenobiotics (not limited to antineoplastic drugs) out of cells (50).…”