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.
Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane ATP‐binding cassette (ABC) ...transporter superfamily is considered one of the primary causes for cancer MDR, in which the role of P‐glycoprotein (P‐gp/ABCB1) has been most well‐established. The clinical co‐administration of P‐gp drug efflux inhibitors, in combination with anticancer drugs which are P‐gp transport substrates, was considered to be a treatment modality to surmount MDR in anticancer therapy by blocking P‐gp‐mediated multidrug efflux. Extensive attempts have been carried out to screen for sets of nontoxic, selective, and efficacious P‐gp efflux inhibitors. In this review, we highlight the recent achievements in drug design, characterization, structure–activity relationship (SAR) studies, and mechanisms of action of the newly synthetic, potent small molecules P‐gp inhibitors in the past 5 years. The development of P‐gp inhibitors will increase our knowledge of the mechanisms and functions of P‐gp‐mediated drug efflux which will benefit drug discovery and clinical cancer therapeutics where P‐gp transporter overexpression has been implicated in MDR.
: ATP-binding cassette (ABC) transporters, especially P-glycoprotein (P-gp), and various metabolic enzymes, in particular, CYP3A, expressed in the small intestine cooperatively limit the absorption ...of orally administered P-gp substrate drugs. The expression and/or function of intestinal P-gp, however, is easily modulated by various factors.
: Through extensive literature searches primarily utilizing PubMed, the authors reviewed factors that may cause inter- or intra-individual variations of the pharmacokinetics of orally administered P-gp substrate drugs due to the modulation of intestinal P-gp expression/function. The information on P-gp modulating factors can help to develop safer and more reliable oral formulations and pharmacotherapy.
: In clinical pharmacotherapy with orally administered P-gp substrate drugs, the pharmacological action may exhibit a large interindividual variation among patients. Factors modulating intestinal P-gp expression/function listed here include: circadian rhythm (or drug dosing time), drug-drug interactions, formulation/excipients (vehicle, nonionic surfactants), food/supplements, gene polymorphism, obesity, colorectal carcinomas, diarrhea, hepatic failure, inflammation, inflammatory bowel disease, ischemia/reperfusion, organ transplant, renal failure, and others. We will discuss the methods for reducing the effect of modulated intestinal P-gp function on the pharmacokinetics of orally administered P-gp substrate drugs to achieve safer and more reliable oral formulations and pharmacotherapy.
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.
Objectives
The inhibitors of P‐glycoprotein (P‐gp) which limits an access of exogenous compounds in the luminal membrane of the intestine have been studied to enhance the intestinal P‐gp‐mediated ...absorption of anticancer drugs.
Methods
Inhibition of the efflux pump by synthesized benzoxanthone derivatives was investigated in vitro and in vivo. MCF‐7/ADR cell line was used for cytotoxicity assay and 3H‐daunomycin (DNM) accumulation/efflux study. Eight benzoxanthone analogues were tested for their effects on DNM cytotoxicity. Among them, three analogues were selected for the accumulation/efflux and P‐gp ATPase studies. Paclitaxel (PTX), a P‐gp substrate anticancer drug, was orally administered to rats with/without compound 1 (8,10‐bis(thiiran‐2‐ylmethoxy)‐7H‐benzocxanthen‐7‐one). The pharmacokinetic parameters of PTX in the presence/absence of compound 1 were evaluated from the plasma concentration‐time profiles.
Key‐findings
Compound 1 increased the DNA accumulation to 6.5‐fold and decreased the DNM efflux to approximately 1/2 in the overexpressing P‐gp cell line. Relative bioavailability (RB) of PTX in rats was significantly increased up to 3.2‐fold by compound 1 (0.5 or 2 mg/kg).
Conclusions
Benzoxanthone analogue, compound 1 is strongly suggested to be a promising inhibitor of P‐gp to improve an oral absorption of compounds for cancer therapy.
Aims
P‐glycoprotein (P‐gp) and CYP3A4‐interacting drugs influence plasma levels of non‐vitamin K antagonist oral anticoagulants (NOACs). However, the clinical relevance is questioned. Therefore, the ...impact of pharmacokinetically‐interacting drugs on the effectiveness and safety of NOACs in patients with atrial fibrillation (AF) was investigated.
Methods
A meta‐analysis was performed based on randomized controlled trials and observational studies retrieved from Pubmed and Embase that investigated the impact of concomitantly used P‐gp/CYP3A4‐interacting drugs on the risk–benefit profile of NOACs in AF patients.
Results
Fifteen studies were included, investigating 21 711 and 306 421 NOAC‐treated AF patients with and without P‐gp/CYP3A4 inhibitor use respectively, while only 1 study included P‐gp/CYP3A4 inducers. In NOAC‐treated AF patients, concomitant use of P‐gp/CYP3A4 inhibitors was associated with significantly higher major bleeding (relative risk RR 1.10, 95% confidence interval CI; 1.01–1.19) and all‐cause mortality risks (RR 1.14, 95%CI 1.05–1.23) compared to not using P‐gp/CYP3A4 inhibitors, while the risks of stroke/systemic embolism (RR 0.88, 95%CI 0.77–1.01), intracranial bleeding (RR 0.89, 95%CI 0.68–1.15) and gastrointestinal bleeding (RR 1.09, 95%CI 0.91–1.30) were not significantly different. Concomitant use of amiodarone with NOACs was associated with lower thromboembolic (RR 0.75, 95%CI 0.61–0.92), similar major bleeding (RR 0.92, 95%CI 0.80–1.07) but higher mortality risks (RR 1.21, 95%CI 1.05–1.39). Coadministration of verapamil or diltiazem was associated with higher major bleeding risks (RR 1.64, 95%CI 1.31–2.06), but comparable thromboembolic (RR 1.10, 95%CI 0.75–1.61) and mortality risks (RR 1.01, 95%CI 0.77–1.33).
Conclusion
Given the higher bleeding and mortality risks in NOAC‐treated AF patients concomitantly using P‐gp/CYP3A4 inhibitors, close monitoring is warranted.
Among the various RNA modifications, adenosine-to-inosine RNA editing, catalyzed by adenosine deaminase acting on RNA (ADAR) family, ADAR1 and ADAR2, is the most common nucleotide conversion in ...mammalian cells. The pathological relevance of ADAR expression has been highlighted in recent human genetic studies. Low expression of the ADAR2 gene is correlated with a poor prognosis in breast cancer patients, but the underlying mechanism remains enigmatic. In this study, we constructed Adar2-knockdown (Adar2-KD) murine breast cancer 4T1 cells and observed their reduced susceptibility to chemotherapeutic drug doxorubicin. Downregulation of ADAR2 induced the expression of P-glycoprotein (P-gp), leading to a reduction in the intracellular accumulation of doxorubicin. The upregulation of P-gp occurred at the post-transcriptional level due to the decreased miR-195a-3p function. The search for the underlying cause of the induction of P-gp expression in Adar2-KD 4T1 cells led to the identification of circular RNA (circRNA) circHif1a as a sponge for miR-195a-3p. The enhanced expression of circHif1a inhibited miR-195a-3p function, resulting in the upregulation of P-gp expression. These results suggest that ADAR2 acts as a suppressor of circHif1a biogenesis and then allows miR-195a-3p to interfere with P-gp translation. Our findings may help to improve drug efficacy by clarifying the mechanism of chemoresistance in breast cancer.
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•RNA editing enzyme ADAR2 is involved in chemoresistance in breast cancer cells.•Downregulation of ADAR2 increases P-glycoprotein, promoting doxorubicin efflux.•Downregulation of ADAR2 induces circHif1a expression.•CircHif1a inhibits miR-195a-3p, resulting in the increased P-glycoprotein expression.
The accumulation of amyloid‐β (Aβ) peptides is a key histopathological feature of the Alzheimer's brain. Defective clearance mechanisms result in toxic levels of soluble Aβ40 and Aβ42 oligomers, ...leading to impaired synaptic function, neurodegeneration and cognitive decline. Growing evidence points to the involvement of P‐glycoprotein (P‐gp or ABCB1), an ATP‐binding cassette transporter highly expressed on the luminal side of the blood–brain barrier, in facilitating the clearance of Aβ from the brain. In this review, we summarise evidence from human, animal and in vitro studies examining the contribution of P‐gp to Aβ clearance, and discuss the potential for P‐gp as a novel pharmacological target in Alzheimer's disease (AD). P‐gp expression and activity in the brain are inversely correlated with ageing, Aβ deposition and AD. Moreover, Aβ itself has been found to compromise the expression of P‐gp, thereby exacerbating Aβ deposition and disease. Despite decades of research, the pathophysiology of AD remains elusive. Understanding the normal versus impaired processing and clearance mechanisms affecting Aβ peptides will assist the development of more effective therapeutic agents to combat this progressive neurodegenerative condition that continues to devastate millions of patients globally.
Defective clearance mechanisms in the Alzheimer's brain lead to the toxic accumulation of amyloid‐β (Aβ) peptides. The multidrug transporter P‐glycoprotein (P‐gp), which regulates the brain environment by exporting compounds across the blood–brain barrier, has also been identified to export Aβ. Here, we discuss the evidence surrounding the contribution of P‐gp to Aβ clearance and Alzheimer's pathophysiology.
This study was aimed to investigate the inhibitory activity of flavonoids on P-glycoprotein (P-gp). Effects of 39 flavonoids on the cellular uptake (CU) of rhodamine123 (Rho) and daunomycin (DNR) ...were investigated in both parental KB and P-gp overexpressed KB/MDR cells. The inhibition mechanism of selected flavonoids was further investigated by measuring the ATPase activity and expression level of P-gp. Twelve flavonoids improved the uptake of Rho (↑RhoF) and nineteen flavonoids increased the uptake of DNR (↑DNRF) in KB/MDR cells with nine flavonoids overlapped. Structure-activity relationship (SAR) indicated that 8-OCH3, and 2′-OH have a negative effect on Rho and DNR transport. Whereas 5-OH, 5-OCH3, 6-OH, 7-OCH3, 3′-OH, and 4′-OH, are essential for inhibition of flavonoids on P-gp and reversing the resistance of Rho and DNR. Eleven selected flavonoids significantly induced the basal P-gp-ATPase activity but much lower than that induced by verapamil. Tangeretin, galangin, kaempferol, quercetin, and morin significantly reversed the ATPase activity stimulated by verapamil. Six of eleven flavonoids significantly decreased P-gp expression, whereas three flavonoids slightly increased P-gp expression. These results provide valuable information that flavonoids can effectively reverse multidrug resistance of P-gp-mediated transport of nutraceutical and drugs by co-administration.
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•39 flavonoids (Fs) were tested for improving Rho or DNR uptake in KB/MDR cells.•12 Fs improved Rho uptake and 19 Fs increased DNR uptake with 9 Fs overlapped.•5-OH, 5-OCH3, 6-OH, 7-OCH3, 3′-OH, and 4′-OH, are essential for inhibition on P-gp.•Fs inhibited P-gp by decreasing its expression and inhibiting its ATPase activity.
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