Natural Products as Alternative Choices for P-Glycoprotein (P-gp) Inhibition

Abstract

Multidrug resistance (MDR) is regarded as one of the bottlenecks of successful clinical treatment for numerous chemotherapeutic agents. Multiple key regulators are alleged to be responsible for MDR and making the treatment regimens ineffective. In this review, we discuss MDR in relation to P-glycoprotein (P-gp) and its down-regulation by natural bioactive molecules. P-gp, a unique ATP-dependent membrane transport protein, is one of those key regulators which are present in the lining of the colon, endothelial cells of the blood brain barrier (BBB), bile duct, adrenal gland, kidney tubules, small intestine, pancreatic ducts and in many other tissues like heart, lungs, spleen, skeletal muscles, etc. Due to its diverse tissue distribution, P-gp is a novel protective barrier to stop the intake of xenobiotics into the human body. Over-expression of P-gp leads to decreased intracellular accretion of many chemotherapeutic agents thus assisting in the development of MDR. Eventually, the effectiveness of these drugs is decreased. P-gp inhibitors act by altering intracellular ATP levels which are the source of energy and/or by affecting membrane contours to increase permeability. However, the use of synthetic inhibitors is known to cause serious toxicities. For this reason, the search for more potent and less toxic P-gp inhibitors of natural origin is underway. The present review aims to recapitulate the research findings on bioactive constituents of natural origin with P-gp inhibition characteristics. Natural bioactive constituents with P-gp modulating effects offer great potential for semi-synthetic modification to produce new scaffolds which could serve as valuable investigative tools to recognize the function of complex ABC transporters apart from evading the systemic toxicities shown by synthetic counterparts. Despite the many published scientific findings encompassing P-gp inhibitors, however, this article stand alones because it provides a vivid picture to the readers pertaining to Pgp inhibitors obtained from natural sources coupled with their mode of action and structures. It provides first-hand information to the scientists working in the field of drug discovery to further synthesise and discover new P-gp inhibitors with less toxicity and more efficacies.

Potentiation of Low-Dose Doxorubicin Cytotoxicity by Affecting P-Glycoprotein through Caryophyllane Sesquiterpenes in HepG2 Cells: an in Vitro and in Silico Study

“…In line with this evidence and taking into account our previous study displaying caryophyllane sesquiterpenes to affect the P-gp-mediated efflux in cancer cells [15,16], we also assessed the effect of the combined treatments on this transporter in hepatoma HepG2 cells and the possible involved mechanisms. P-gp, also known as MDR1 or ABCB1, is an energy-dependent drug efflux pump, encoded by the human mdr1 gene, and plays a pivotal role in drug pharmacokinetics and permeability [65]. Its overexpression makes some tumors resistant to anticancer drugs, due to their decreased intracellular accumulation, thus suggesting it could represent a possible strategy to reverse cancer multidrug resistance [66].…”

Long-Chain Metabolites of Vitamin E: Metabolic Activation as a General Concept for Lipid-Soluble Vitamins?

“…The interaction of the vitamin E LCMs with pharmaceuticals was tested by analyzing the regulation of P-glycoprotein (P-gp). P-gp regulates, inter alia, the intracellular concentration of pharmaceuticals and its expression is regulated by various transcription factors, including heat shock transcription factor 1, nuclear factor Y and the pregnane X receptor (PXR) [ 104 , 105 ].…”

Administration of Vitamin D Metabolites Affects RNA Expression of Xenobiotic Metabolising Enzymes and Function of ABC Transporters in Rats

“…Inhibition of P-gp cannot only occur by influencing its expression but also by alteration of the ATPase activity or competition for binding sites. Although verapamil competes with other substrates for the P-gp binding sites, it also increases its ATPase activity [48]. Progesterone and desoxycorticosterone diminish this stimulating effect of verapamil in a dosedependent manner [49].…”