What is the role of P-glycoprotein in multi drug resistant cancers?
P-glycoprotein (P-gp) is a key player in the multidrug-resistant phenotype in cancer. The protein confers resistance by mediating the ATP-dependent efflux of an astonishing array of anticancer drugs.
Where is P-gp found?
P-gp is primarily expressed in the liver, kidney, gastrointestinal tract, and blood brain barrier. P-gp is located on the canalicular apical membrane of hepatocytes in the liver; on the brush border of proximal tubule cells in the kidney; and on the apical membrane of mucosal cells in the small intestine (3).
What is P-glycoprotein inhibitor?
P-gp is overexpressed on the surface of cancer cells and prevents drug accumulation inside the tumor, acting as the efflux pump. It extrudes anticancer drugs before they can reach the intended target. Further, it often mediates the development of resistance of the cells to anticancer drugs.
What anticancer drugs are affected by P-glycoprotein?
A plethora of anticancer drugs that are central to many chemotherapeutic regimes are susceptible to P-gp-mediated efflux (Figure 1), such as the microtubule-targeting vinca alkaloids (e.g. vinblastine and vincristine) and taxanes (paclitaxel and docetaxel), the DNA-chelating anthracyclines (doxorubicin and daunorubicin …
What are P-glycoprotein inhibitors?
Inhibition of P-glycoprotein to prevent drug efflux. P-gp inhibitors are classified into three generations based on their specificity, affinity, and toxicity. First generation inhibitors are pharmacologically active substances which are clinically used for specific treatments but have the ability to inhibit P-gp.
What anticancer drugs would be affected by P-glycoprotein?
What are P-gp drugs?
Examples of drugs that are substrates of P-gp efflux pump include: Apixaban, colchicine, cyclosporine, dabigatran, digoxin, edoxaban, rivaroxaban, and tacrolimus. The degree of effect on P-gp substrate serum concentration may be altered by dose and timing of orally administered P-gp inhibitor or inducer.
What does the P stand for in P-glycoprotein?
P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein of the cell membrane that pumps many foreign substances out of cells.
Who discovered P-glycoprotein?
The curiosities of MDR drove Ling, now collaborating with other scientists in Toronto, to identify the protein that caused it. This effort led to the identification of a protein that was termed P-glycoprotein (P-gp) (Figure 3), due to its association with colchicine permeability (1).
What drugs are P glycoprotein inhibitors?
Some common pharmacological inhibitors of P-glycoprotein include: amiodarone, clarithromycin, ciclosporin, colchicine, diltiazem, erythromycin, felodipine, ketoconazole, lansoprazole, omeprazole and other proton-pump inhibitors, nifedipine, paroxetine, reserpine, saquinavir, sertraline, quinidine, tamoxifen, verapamil.
What drugs are BCRP inhibitors?
BCRP inhibitors include, among others, fumitremorgin C (FTC), the FTC analogue Ko143, the acridone carboxamide derivative GF120918, anti-HIV protease inhibitors nelfinavir and ritonavir, the dietary flavonoids chrysin and biochanin A, the tyrosine kinase inhibitors gefitinib and imatinib [5, 16, 36], and herb extracts …
How can P-glycoprotein be reduced?
In general, P-gp can be inhibited by three mechanisms: (i) blocking drug binding site either competitively, non-competitively (Fig. 2) or allosterically; (ii) interfering with ATP hydrolysis; and (iii) altering integrity of cell membrane lipids.
What is P-glycoprotein (P-gp)?
1 Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Shandong Province, P.R. China. P-glycoprotein (P-gp) is an ATP-driven transmembrane transporter capable of effluxing a wide variety of structurally diverse and functionally unrelated hydrophobic compounds out of the cell.
What is the function of apical glycoprotein?
P-glycoprotein is found in the apical (luminal) membrane of the entire intestine from duodenum to rectum, with a high expression in the enterocytes of the small intestine. It reduces the oral availability of drugs that are its substrates. 3,4
How do substrates of P-glycoprotein affect drug activity?
Like the enzymes involved in drug metabolism, substrates of P-glycoprotein can potentially act as inhibitors or inducers of its function. Inhibition of P-glycoprotein can result in increased bioavailability of the susceptible drug.
What are the drug-drug interactions of glycoprotein?
Drug interactions. P-glycoprotein is an important mediator of drug-drug interactions.3 The pharmacokinetics of a drug may be altered when co-administered with compounds which inhibit or induce P-glycoprotein.3,5,6 Inhibitors include clarithromycin, erythromycin, ritonavir and verapamil.