P-Glycoprotein: One Mechanism, Many Tasks and the Consequences for Pharmacotherapy of Cancers

Abstract

P-glycoprotein or multidrug resistance protein (MDR1) is an adenosine triphosphate (ATP) binding cassette transporter (ABCB1) intensely investigated because it is an obstacle to successful pharmacotherapy of cancers. P-glycoprotein prevents cellular uptake of a large number of structurally and functionally diverse compounds, including most cancer therapeutics and in this way causes multidrug resistance (MDR). To overcome MDR, and thus improve cancer treatment, an understanding of P-glycoprotein inhibition at the molecular level is required. With this goal in mind, we propose rules that predict whether a compound is a modulator, substrate, inhibitor, or inducer of P-glycoprotein. This new set of rules is derived from a quantitative analysis of the drug binding and transport properties of P-glycoprotein. We further discuss the role of P-glycoprotein in immune surveillance and cell metabolism. Finally, the predictive power of the proposed rules is demonstrated with a set of FDA approved drugs which have been repurposed for cancer therapy.

Comparative in silico prediction of P‐glycoprotein‐mediated transport for 2010–2020 US FDA‐approved drugs using six Web‐tools

“…Interestingly, analysis of the test set with respect to some physicochemical properties indicated that 17/24 molecular descriptors exhibited significantly different values according to the FDA‐related P‐gp status (Table S3). Notably, P‐gp substrates display higher molecular weight (MW), total surface area (SAtot) and volume parameters (McGowan volume/Vx and van der Waals volume from McGowan volume/VvdwMG) than P‐gp non‐substrates, which agrees with previous studies (Bain et al., 1997; Seelig, 2020). By contrast, the lipophilicity parameters Moriguchi LogP (MLOGP) and Ghose‐Crippen LogP (ALOGP) were not associated with P‐gp status (Table S3).…”

Cryo-EM structure of an elusive pre-transport intermediate of the multidrug ABC transporter BmrCD reveals modes of asymmetric drug binding

“…A second, heterodimer-specific mechanistic gap, pertains to the nature of drug binding. Efforts to sensitize drug-resistant cells to various small molecules and chemotherapeutics by inhibiting efflux pumps such as heterodimeric ABC transporters has not yet proven successful 10,11 . In the absence of a detailed understanding of determinants of transporter/drug interactions, progress on this front remains stalled.…”

S-Adenosylmethionine Increases the Sensitivity of Human Colorectal Cancer Cells to 5-Fluorouracil by Inhibiting P-Glycoprotein Expression and NF-κB Activation

“…The P-gp transporter, also referred to as ATP-binding cassette subfamily B member 1 (ABCB1) or multidrug resistance protein 1 (MDR1), is among the most clinically important ABC transporters [32,33]. Physiologically, P-gp is constitutively expressed in cells with specific barrier functions, such as the intestine where it is involved in the detoxification of xenobiotics, while in cancer cells P-gp functions as an energy-driven efflux pump which induces a significant reduction in intracellular accumulation of drugs, decreasing the efficacy of chemotherapy and ultimately causing MDR.…”

“…Conversely, pretreatment of cells with AdoMet inhibited 5-FU-induced activation of the autophagic process as detected by red staining (Figures 4A,B Several tumor cells overexpress P-gp causing failure of chemotherapy due to an increased efflux of drug molecules from the cancer cells and thereby resulting in a decrease in intracellular drug concentration. This mechanism ultimately determines drug resistance [32,33].…”