Disrupting P-glycoprotein function in clinical settings: what can we learn from the fundamental aspects of this transporter?

Abstract

P-glycoprotein is one of the most well-studied drug transporters, significant for its role in cancer multiple drug resistance. However, using P-gp inhibitors with the aim of enhancing the therapeutic efficacy of anti-cancer drugs has led to disappointing outcomes. Furthermore, several lead compounds suggested by in vitro and pre-clinical studies have shown variable pharmacokinetics and therapeutic efficacies when applied in the clinical setting. This review will highlight the need to revisit a sound approach to better design and apply P-gp inhibitors in light of safety and efficacy. Challenges confronting the issue hinge upon myriad studies that do not necessarily represent the heterogeneous target population of this therapeutic approach. The application of P-gp modulators has also been complicated by the promiscuous substrate-binding behaviour of P-gp, as well as toxicities related to its intrinsic presence in healthy tissue. This review capitalizes on information spanning genetics, energetics, and pharmacology, bringing to light some fundamental aspects that ought to be reconsidered in order to improve upon and design the next generation of P-gp inhibitors.

Keywords: Cancer therapeutics; P-glycoprotein; drug resistance; energetics; pharmacokinetics; transporter.

Figure 1

Expanded framework for the application of P-gp inhibitors in the clinical setting. There is an elevated energy demand in cancer cells, presenting novel opportunities for targeting metabolic pathways. The excellent coping mechanism of cancer cells given metabolic stress may be a contributor to drug resistance development, possibly in concert with P-gp regulation and its reliance on the overall energetic status of the cell. P-gp has also been associated with the suppression of the apoptotic signaling pathway, favoring cell survival over cell death. The outcome of cancer therapy may have strong correlations with MDR1 expression, P-gp activity, and cellular energetics, warranting a more comprehensive foundation for pre-clinical studies and rational drug design. Thus, a better understanding of the profound roles of P-gp in cancer would be necessary to improve current treatment programs.

Figure 2

Graphical representation of various interactions of P-gp with the cancer cell. (1) The anti-cancer drug (substrate, S) is initially present extracellularly, and must enter the plasma membrane to exert its therapeutic activity (2). Here, it is subject to transport and partitioning at the lipid bilayer. At the inner leaflet (3), it encounters the transmembrane domain of P-gp and is effluxed (4) with concomitant hydrolysis of ATP. A P-gp inhibitor (Inh), upon binding to P-gp (5), may trigger changes in ATP demand (6). An associated effect of P-gp stimulation is extracellular acidification (7), although the precise mechanism of this symport-like activity is still unknown. Acidification of the extracellular compartment may alter the chemistry of the inhibitor or drug substrate, changing their distribution patterns across the extracellular and intracellular compartments, as well as within the lipid bilayer. This event may further support drug resistance development. The substrate and inhibitor may also activate transcription factors (TF) that modulate P-gp expression (8). The broken lines represent speculative relationships.