-
Central Nervous System Agents in... Sep 2011A major component in the protection of the brain against blood-borne toxic influences is the multispecific efflux pump P-glycoprotein. This pump, a 170 kD protein,... (Review)
Review
A major component in the protection of the brain against blood-borne toxic influences is the multispecific efflux pump P-glycoprotein. This pump, a 170 kD protein, located at the luminal side of the capillary endothelial cells, has a large capacity and is capable of extruding a wide array of structurally divergent substrates. The brain uptake of the majority of antidepressants and antipsychotics, as well as many other psychotropic drugs and endogenous compounds is hampered by the activity of P-glycoprotein. In this review we discuss the current state of knowledge concerning the role of Pglycoprotein on pharmacokinetics of psychiatric drugs and the impact of modulation of P-glycoprotein on major psychiatric disorders. Relevant issues in reference to the function of P-glycoprotein and other efflux pumps in the blood-brain barrier related to mood disorders and schizophrenia are addressed, such as a possible role of P-glycoprotein as a susceptibility factor in depressive disorders and psychotic disorders.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Aging; Blood-Brain Barrier; Brain; Humans; Mental Disorders; Models, Molecular; Nerve Degeneration; Psychotropic Drugs; Stress, Psychological; Substrate Specificity
PubMed: 21919870
DOI: 10.2174/187152411798047744 -
Anti-cancer Agents in Medicinal... Jan 2013Multidrug resistance (MDR) of cancer tissue is a phenomenon in which cancer cells exhibit reduced sensitivity to a large group of unrelated drugs with different... (Review)
Review
Multidrug resistance (MDR) of cancer tissue is a phenomenon in which cancer cells exhibit reduced sensitivity to a large group of unrelated drugs with different mechanisms of pharmacological activity. Mechanisms that reduce cell sensitivity to damage induced by a variety of chemicals were found to be caused by diverse, albeit well-defined, phenotypic alterations. The molecular basis of MDR commonly involves overexpression of the plasma membrane drug efflux pump - P-glycoprotein (P-gp). This glycoprotein is an ABCB1 member of the ABC transporter family. Cells that develop MDR of this type express massive amounts of P-gp that can induce a drug resistance of more than 100 times higher than normal cells to several drugs, which are substrates of P-gp. Expression of P-gp could be inherent to cancer cells with regard to the specialized tissues from which the cells originated. This is often designated as intrinsic Pgp- mediated MDR. However, overexpression of P-gp may be induced by selection and/or adaptation of cells during exposure to anticancer drugs; this particular example is known as acquired P-gp-mediated MDR. Drugs that are potential inducers of P-gp are often substrates of this transporter. However, several substances that have been proven to not be transportable by P-gp (such as cisplatin or alltrans retinoic acid) could induce minor improvements in P-gp overexpression. It is generally accepted that the drug efflux activity of Pgp is a major cause of reduced cell sensitivity to several compounds. However, P-gp may have side effects that are independent of its drug efflux activity. Several authors have described a direct influence of P-gp on the function of proteins involved in regulatory pathways, including apoptotic progression (such as p53, caspase-3 and Pokemon). Moreover, alterations of cell regulatory pathways, including protein expression, glycosylation and phosphorylation, have been demonstrated in cells overexpressing P-gp, which may consequently induce changes in cell sensitivity to substances that are not P-gp substrates or modulators. We recently reported that P-gppositive L1210 cells exhibit reduced sensitivity to cisplatin, concanavalin A, thapsigargin and tunicamycin. Thus, P-gp-mediated MDR represents a more complex process than was expected, and the unintended effects of P-gp overexpression should be considered when describing this phenotype. The present review aims to provide the most current informations about P-gp-mediated MDR while paying particular attention to the possible dual function of this protein as a drug efflux pump and a regulatory protein that influences diverse cell processes. From a clinical standpoint, overexpression of P-gp in cancer cells represents a real obstacle to effective chemotherapy for malignant diseases. Therefore, this protein should be considered as a viable target for pharmaceutical design.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Apoptosis; Drug Resistance, Neoplasm; Glycosylation; Humans; Neoplasms; Protein Kinases
PubMed: 22931413
DOI: No ID Found -
Trends in Pharmacological Sciences Aug 2004P-glycoprotein is the product of the ABCB1 [also known as multidrug resistance 1 (MDR1)] gene. It translocates a broad variety of xenobiotics out of cells.... (Review)
Review
P-glycoprotein is the product of the ABCB1 [also known as multidrug resistance 1 (MDR1)] gene. It translocates a broad variety of xenobiotics out of cells. P-glycoprotein was first described in tumor cells that were resistant to various anticancer agents as a result of P-glycoprotein overexpression. P-glycoprotein is not only expressed in tumor cells but also in a broad variety of normal tissues with excretory function (small intestine, liver and kidney) and at blood-tissue barriers (blood-brain barrier, blood-testis barrier and placenta). In particular, following the generation of P-glycoprotein-deficient mice it became clear that this efflux transporter limits the absorption of orally administered drugs, promotes drug elimination into bile and urine, and protects various tissues (e.g. brain, testis and fetus) from potentially toxic xenobiotics. In humans, a considerable interindividual variability in P-glycoprotein tissue expression is observed, and current research is focused on the potential role of ABCB1 polymorphisms and haplotypes that affect P-glycoprotein tissue expression, plasma concentrations of drugs, the frequency of adverse drug reactions and treatment outcome.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Blood-Brain Barrier; Blood-Testis Barrier; Humans; Intestinal Mucosa; Kidney; Liver; Pharmaceutical Preparations; Pharmacokinetics; Placenta
PubMed: 15276711
DOI: 10.1016/j.tips.2004.06.002 -
Journal of Drug Targeting Sep 2022Chemotherapy is the mainstay in cancer treatment; however, its application is clinically limited to patients with multidrug resistance (MDR). MDR reverses the role of... (Review)
Review
Chemotherapy is the mainstay in cancer treatment; however, its application is clinically limited to patients with multidrug resistance (MDR). MDR reverses the role of chemotherapy through significant attribution to pharmacokinetic characteristics, where ATP-binding cassette transporter proteins, P-glycoprotein (P-gp), pump out the intracellularly transported chemotherapeutics from the cancer cells. Therefore, overexpression of such receptors on MDR cancer cell surfaces tends to decrease the efficacy of a large number of existing chemotherapeutics. P-gp inhibitors, especially of natural origin, play a vital role in enhancing the cellular concentration of clinically applicable chemotherapeutics. Therefore, co-administration of these natural P-gp inhibitors with chemotherapeutics could improve chemotherapeutic efficacy against MDR cancer, which has been evidenced in the literature. Co-delivery of these therapeutic components can effectively be made using the emerging nanotechnology platform, which could facilitate controlled delivery of the incorporated components to the cancerous microenvironment, through passive and active targeting. Thereby, cellular retention of chemotherapeutic agents by the P-gp mediated inhibitory effect on the efflux pump using the nanocarrier co-delivery platform could improve the anticancer potential of the chemotherapeutics. This review has presented the advancement of naturally occurring P-gp inhibitors as a promising adjuvant in chemotherapy to modulate the pharmacokinetic properties of chemotherapeutic agents using the nanotechnology platform.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Nanoparticle Drug Delivery System; Neoplasms; Tumor Microenvironment
PubMed: 35465812
DOI: 10.1080/1061186X.2022.2069782 -
Biochemical Society Transactions Oct 2015It is almost 40 years since the drug efflux pump P-glycoprotein (permeability glycoprotein or P-gp) was shown to confer multi-drug resistance in cancer cells. This... (Review)
Review
It is almost 40 years since the drug efflux pump P-glycoprotein (permeability glycoprotein or P-gp) was shown to confer multi-drug resistance in cancer cells. This protein has been one of the most extensively investigated transport proteins due to its intriguing mechanism and its affect in oncology. P-gp is known to interact with over 300 compounds and the ability to achieve this has not yet been revealed. Following the binding of substrate and nucleotide, a complex series of conformational changes in the membrane and cytosolic domains translocates substrate across the membrane. Despite over 30 years of biochemical investigation, the availability of structural data and a plethora of chemical tools to modulate its function, the molecular mechanism remains a mystery. In addition, overcoming its activity in resistant cancer cells has not been achieved in the clinic, thereby garnering some degree of pessimism in the field. This review highlights the progress that has been achieved in understanding this complex protein and the value of undertaking molecular studies.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adenosine Triphosphate; Biological Transport; Crystallography, X-Ray; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms; Pharmaceutical Preparations; Protein Binding
PubMed: 26517914
DOI: 10.1042/BST20150131 -
Physiological Reviews Apr 1997Most cancer deaths result from the cancer's either being intrinsically resistant to chemotherapeutic drugs or becoming resistant after being initially sensitive. Often,... (Review)
Review
Most cancer deaths result from the cancer's either being intrinsically resistant to chemotherapeutic drugs or becoming resistant after being initially sensitive. Often, in cells grown in cell culture, drug resistance correlates with the presence of one or more of the so-called P-glycoproteins or multidrug resistance proteins, products of the mdr family of genes. This review is largely concerned with the transport kinetics of the P-glycoproteins. We first present a brief overview of the P-glycoproteins, their properties, and their clinical significance. Later sections of the review expand on this material with special emphasis on the substrates of P-glycoprotein and how they cross the cell membrane, on the transport kinetics of the P-glycoprotein, on reversers of its action, and on its activity as an ATPase. In a final section, we consider the mechanism of action of P-glycoprotein as an actively transporting membrane pump. The characteristic of P-glycoprotein considered the most difficult to explain is its very broad specificity (or lack of specificity), but there are precedents for this property in well-known proteins such as serum albumin, which binds a range of molecular types, including substrates and reversers of P-glycoprotein, seemingly as broad as does P-glycoprotein. Pointing out this analogy does not provide a molecular explanation for the substrate-binding properties of P-glycoprotein but does make those properties more assimilable.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Drug Resistance, Multiple; Humans; Kinetics; Models, Biological; Molecular Biology; Mutagenesis, Site-Directed
PubMed: 9114823
DOI: 10.1152/physrev.1997.77.2.545 -
Leukemia Jul 1997Multidrug resistance (MDR) is one of the major obstacles to successful cancer chemotherapy. Since P-glycoprotein (P-gp) encoded by the MDR-1 gene plays a key role in... (Review)
Review
Multidrug resistance (MDR) is one of the major obstacles to successful cancer chemotherapy. Since P-glycoprotein (P-gp) encoded by the MDR-1 gene plays a key role in MDR, many P-gp-specific monoclonal antibodies (MAbs) have been generated for characterization and analysis of P-gp. Among those antibodies, MRK16 has been widely used not only for elucidation of the mechanisms of P-gp-mediated MDR but also for diagnostic and therapeutic studies. Two types of magnetic cell sorting assays, termed MRK16-MACS and MRK16-MACS-FACS, have been established by us and may offer a useful tool to quantitate low levels of P-gp expression. This article describes the characteristics of the antibodies against P-gp and discuss the diagnostic implications of the antibodies.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antibodies, Monoclonal; Drug Resistance, Multiple; Flow Cytometry; Humans; Mice; Polymerase Chain Reaction
PubMed: 9205000
DOI: 10.1038/sj.leu.2400658 -
Current Drug Targets Jul 2000Multidrug resistance (MDR) is a major obstacle to successful cancer chemotherapy. One important mechanism of MDR involves the multidrug transporter, P-glycoprotein... (Review)
Review
Multidrug resistance (MDR) is a major obstacle to successful cancer chemotherapy. One important mechanism of MDR involves the multidrug transporter, P-glycoprotein (Pgp), which confers upon cancer cells the ability to resist lethal doses of certain cytotoxic drugs by pumping the drugs out of the cells and thus reducing their cytotoxicity. Pgp belongs to the ATP-binding cassette (ABC) family of transporter molecules which require hydrolysis of ATP to run the transport mechanism. The substrates of Pgp may be endogenous (steroid hormones, cytokines) or exogenous (cytostatic drugs). A number of studies have demonstrated a negative correlation between Pgp expression levels and chemosensitivity or survival in a range of human malignancies. In principle, Pgp mediated drug resistance can be circumvented by treatment regimens that either exclude Pgp substrate drugs or include Pgp inhibitory agents. Experimental studies have demonstrated that certain structural modifications of anthracyclines confer the ability to escape Pgp transport. The therapeutic benefit of Pgp inhibitors as chemosensitizers is currently being explored in phase III clinical trials, and the first promising results have already been reported. Another therapeutic option for Pgp inhibitors has recently evolved as several Pgp inhibitors, many of which are generally low-toxic substances, by themselves constrain proliferation and cause cell death by apoptosis in certain MDR cancer cell lines. The dual effect of Pgp inhibitors, targeting MDR cancer cells selectively, may translate into improved efficacy of cancer chemotherapy and perhaps new and less toxic drug treatment strategies in human MDR cancer.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Apoptosis; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms; RNA, Messenger
PubMed: 11475537
DOI: 10.2174/1389450003349443 -
Expert Review of Anticancer Therapy Apr 2007P-glycoprotein actively transports structurally unrelated compounds out of cells, conferring the multidrug resistance phenotype in cancer. Tariquidar is a potent,... (Review)
Review
P-glycoprotein actively transports structurally unrelated compounds out of cells, conferring the multidrug resistance phenotype in cancer. Tariquidar is a potent, specific, noncompetitive inhibitor of P-glycoprotein. Tariquidar inhibits the ATPase activity of P-glycoprotein, suggesting that the modulating effect is derived from the inhibition of substrate binding, inhibition of ATP hydrolysis or both. In clinical trials, tariquidar is tolerable and does not have significant pharmacokinetic interaction with chemotherapy. In patients, inhibition of P-glycoprotein has been demonstrated for 48 h after a single dose of tariquidar. Studies to assess a possible increase in toxicity of chemotherapy and the impact of P-glycoprotein inhibition on tumor response and patient outcome are ongoing. Tariquidar can be considered an ideal agent for testing the role of P-glycoprotein inhibition in cancer.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms; Protein Transport; Quinolines
PubMed: 17428165
DOI: 10.1586/14737140.7.4.447 -
Journal of Bioenergetics and... Dec 2007The development of effective clinical interventions against multidrug resistance (MDR) in cancer remains a significant challenge. Single nucleotide polymorphisms (SNPs)... (Review)
Review
The development of effective clinical interventions against multidrug resistance (MDR) in cancer remains a significant challenge. Single nucleotide polymorphisms (SNPs) contribute to wide variations in how individuals respond to medications and there are several SNPs in human P-glycoprotein (P-gp) that may influence the interactions of drug-substrates with the transporter. Interestingly, even some of the synonymous SNPs have functional consequences for P-gp. It is also becoming increasingly evident that an understanding of the transport pathway of P-gp may be necessary to design effective modulators. In this review we discuss: (1) The potential importance of SNPs (both synonymous and non-synonymous) in MDR and (2) How new concepts that have emerged from structural studies with isolated nucleotide binding domains of bacterial ABC transporters have prompted biochemical studies on P-gp, leading to a better understanding of the mechanism of P-gp mediated transport. Our results suggest that the power-stroke is provided only after formation of the pre-hydrolysis transition-like (E.S) state during ATP hydrolysis.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Bacterial Proteins; Binding Sites; Biological Transport; Drug Resistance, Multiple; Genes, MDR; Genome, Human; Humans; Polymorphism, Single Nucleotide; Protein Structure, Tertiary
PubMed: 18058211
DOI: 10.1007/s10863-007-9115-9