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Seminars in Oncology Dec 2005Previously untreated breast cancer is relatively sensitive to a range of anticancer drugs. However, exposure to these drugs is often followed by acquisition of multidrug... (Meta-Analysis)
Meta-Analysis Review
Previously untreated breast cancer is relatively sensitive to a range of anticancer drugs. However, exposure to these drugs is often followed by acquisition of multidrug resistance, which is associated with a significantly worse outcome. One of the more widely studied mechanisms of drug resistance is the function of P-glycoprotein (P-gp), a membrane transporter with a wide range of substrates, including several anticancer agents, and a member of the ATP-binding cassette superfamily of proteins. A review of the published literature indicates that P-gp expression is detected in a significant percentage of breast cancers. Moreover, P-gp expression is increased after exposure to chemotherapeutic drugs (particularly those known to be P-gp substrates), and correlates with a worse response to treatment, especially when detected following treatment, in both the adjuvant and neoadjuvant settings. Consequently, P-gp represents a potential biomarker of drug resistance. However, a direct role of P-gp as a cause of clinical drug resistance has not been adequately tested in breast cancer. Future studies aimed at validating the mechanistic role of P-gp should include trials of multidrug resistance reversal using P-gp-specific inhibitors and relating results to the levels of P-gp expression. Future studies should also take into account the potentially multifactorial nature of multidrug resistance.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Antineoplastic Agents; Breast Neoplasms; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans
PubMed: 16360717
DOI: 10.1053/j.seminoncol.2005.09.009 -
Journal of Enzyme Inhibition and... Dec 2016Multidrug resistance (MDR) has emerged as the main problem in anti-cancer therapy. Although MDR involves complex factors and processes, the main pivot is the expression... (Review)
Review
Multidrug resistance (MDR) has emerged as the main problem in anti-cancer therapy. Although MDR involves complex factors and processes, the main pivot is the expression of multidrug efflux pumps. P-glycoprotein (P-gp) belongs to the family of adenosine triphosphate (ATP)-binding cassette (ABC) transporters. It functions in cellular detoxification, pumping a wide range of xenobiotic compounds out of the cell. An attractive therapeutic strategy for overcoming MDR is to inhibit the transport function of P-gp and thus, increase intracellular concentration of drugs. Recently, various types of P-gp inhibitors have been found and used in experiments. However, none of them has passed clinical trials due to their high side-effects. Hence, the search for alternatives, such as plant-based P-gp inhibitors have gained attention recently. Therefore, we give an overview of the source, function, structure and mechanism of plant-based P-gp inhibitors and give more attention to cancer-related studies. These products could be the future potential drug candidates for further research as P-gp inhibitors.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents, Phytogenic; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms
PubMed: 26932198
DOI: 10.3109/14756366.2016.1149476 -
Drug News & Perspectives Sep 2009Epilepsy affects more than 60 million people worldwide. While most patients can be treated with antiepileptic drugs, up to 40% of patients respond poorly to... (Review)
Review
Epilepsy affects more than 60 million people worldwide. While most patients can be treated with antiepileptic drugs, up to 40% of patients respond poorly to pharmacotherapy. This drug resistance is not well understood and presents a major clinical problem. In this short review we provide background information on one potential cause of antiepileptic drug resistance, namely, upregulation of the drug efflux transporter P-glycoprotein at the blood-brain barrier. We summarize recent findings that connect antiepileptic drug resistance with P-glycoprotein upregulation and show a mechanistic link between seizures and upregulation of this transporter. We provide an overview of results demonstrating that glutamate released during seizures signals through N-methyl-Daspartate (NMDA) receptor and cyclooxygenase-2 (COX-2) to increase P-glycoprotein. In this context we discuss the NMDA receptor and COX-2 as potential therapeutic targets and provide information on current clinical trials on drugresistant epilepsy involving blood-brain barrier efflux transporters. Finally, we provide a perspective on future research that could help improve the treatment of drug-resistant epilepsy.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Anticonvulsants; Drug Resistance; Epilepsy; Humans; Signal Transduction; Up-Regulation
PubMed: 19890496
DOI: 10.1358/dnp.2009.22.7.1401354 -
The American Journal of Medicine Dec 1995
Review
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Drug Resistance; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Rats; Structure-Activity Relationship
PubMed: 8585532
DOI: 10.1016/s0002-9343(99)80283-6 -
Drug Discovery Today Apr 2012The impact of P-glycoprotein (P-gp) on the multidrug resistance and pharmacokinetics of clinically important drugs has been widely recognized. Here, we review in silico... (Review)
Review
The impact of P-glycoprotein (P-gp) on the multidrug resistance and pharmacokinetics of clinically important drugs has been widely recognized. Here, we review in silico approaches and computational models for identifying substrates or inhibitors of P-gp. The advances in the datasets for model building and available computational models are summarized and the advantages and drawbacks of these models are outlined. We also discuss the impact of the recently reported crystal structures of P-gp on potential breakthroughs in the computational modeling of P-gp substrates. Finally, the challenges of developing reliable prediction models for P-gp inhibitors or substrates, as well as the strategies to surmount these challenges, are reviewed.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Computer Simulation; Drug Resistance, Multiple; Humans; Models, Chemical; Models, Molecular; Pharmaceutical Preparations
PubMed: 22119877
DOI: 10.1016/j.drudis.2011.11.003 -
Medical Science Monitor : International... Jan 2004This article reviews recent advances in our understanding of the structure, drug interaction mechanism, and substrate molecular requirements of P-glycoprotein (P-gp) and... (Review)
Review
This article reviews recent advances in our understanding of the structure, drug interaction mechanism, and substrate molecular requirements of P-glycoprotein (P-gp) and its emerging crucial role in drug disposition and the modulation of drug interaction. In view of its wide localization in normal tissues, the broad variety of structurally and functionally unrelated substrates of P-gp, and its ATP-dependent outward-oriented transport, P-gp actively participates in intestinal secretion, blood-tissue barriers, and biliary and renal excretions for many exogenous substrates, and also performs a protective role to prevent entry of xenobiotics. Moreover, the importance of P-gp-mediated drug interactions in clinical practice can hardly be underestimated, since it may result in severe side effects, such as digitalis drug interaction. Polymorphism or single nucleotide polymorphism (SNP) associated with P-gp may exert a significant effect on the pharmacokinetic behavior of its substrates, a fact which has major clinical implications and suggests careful dose adjustment for individual treatment. Moreover, dietary components and pharmaceutical excipients may modulate P-gp activity, and as a result affect in vivo drug disposition and therapeutic efficacy; examples include grapefruit juice, Pluronic P85, PEG 300, etc. In summary, it should be emphasized that P-gp is an integral component in the process of drug discovery, development strategy,
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Diet; Drug Interactions; Drug Resistance, Multiple; Excipients; Humans; Intestinal Absorption; Models, Molecular; Molecular Structure; Pharmacokinetics; Tissue Distribution
PubMed: 14704647
DOI: No ID Found -
Handbook of Experimental Pharmacology 2011P-glycoprotein (ABCB1) is one of the most extensively studied transporters regarding drug resistance and drug-drug interactions. P-glycoprotein is expressed in multiple... (Review)
Review
P-glycoprotein (ABCB1) is one of the most extensively studied transporters regarding drug resistance and drug-drug interactions. P-glycoprotein is expressed in multiple key organs in drug disposition such as small intestine, blood-brain barrier, kidney, and liver. Therefore, P-glycoprotein mediated drug-drug interactions can occur at various organs and tissues. This chapter will mainly focus on drug-drug interactions that are mediated by the intestinal P-glycoprotein.During the last decade, many in vitro and in vivo studies reported that the induction or inhibition of P-glycoprotein can lead to drug-drug interactions. For instance, induction of the intestinal P-glycoprotein activity can cause reduced bioavailability of orally administered drugs and decreased therapeutic efficacy. On the other hand, the inhibition of the intestinal P-glycoprotein activity can lead to increased bioavailability, thus leading to an increased risk of adverse side effects.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Biological Availability; Biological Transport; Drug Interactions; Humans; Intestinal Mucosa; Intestines; Pharmaceutical Preparations; Up-Regulation
PubMed: 21103973
DOI: 10.1007/978-3-642-14541-4_7 -
Xenobiotica; the Fate of Foreign... Nov 20131. The efflux pump p-glycoprotein (P-gp/ABCB1) has received enormous attention in drug (xenobiotic) disposition due to its role in modulation of the drug availability... (Review)
Review
1. The efflux pump p-glycoprotein (P-gp/ABCB1) has received enormous attention in drug (xenobiotic) disposition due to its role in modulation of the drug availability and in protection of sensitive organs. 2. P-gp mediated efflux is one of main mechanisms for multidrug resistance in cancer cells. A main approach to reverse the resistance and restore the drug efficacy is to use specific inhibitors of P-gp that suppress the efflux activity. 3. This review summarizes the binding capabilities of known chemical inhibitors based on the analyses of structure-activity relationships, and computational modeling of the inhibitors as well as the binding site of P-gp protein. 4. The molecular models will facilitate the design of lead inhibitors as drug candidates. Also, it helps scientists in early drug discovery phase to synthesize chemical series with better understanding of their P-gp binding liabilities.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Benzophenones; Computer Simulation; Humans; Models, Molecular; Propafenone; Structure-Activity Relationship
PubMed: 23617855
DOI: 10.3109/00498254.2013.791003 -
Current Cancer Drug Targets Feb 2008Oral anticancer drug treatment represents a significant change to current oncology practice. Support for oral anticancer treatment is driven by issues of... (Review)
Review
Oral anticancer drug treatment represents a significant change to current oncology practice. Support for oral anticancer treatment is driven by issues of pharmacoeconomics, accommodating the need for protracted drug administration for many emerging cytostatic therapies, response to patient preference and in improving patient quality of life. Much focus has concentrated on defining the cellular mechanisms underlying the pharmacokinetic limitations associated with the oral route of administration. However, the potential effects of oral anticancer drugs on gut associated host mediated immunity have been overlooked. Given that the immune system is central for tumour rejection, an assessment of the potential effects oral anticancer drugs may have at this level, and the impact of this on the treatment of gastrointestinal malignancy is of significant clinical importance. P-glycoprotein is a multidrug transporter that contributes to the reduced bioavailability of many orally administered medications. P-glycoprotein achieves this by virtue of its drug efflux capacity at the level of the gut epithelia. P-glycoprotein is also notorious for contributing to the multidrug resistance phenotype observed in many drug refractory human cancers. Likewise, this drug transporter serves a role in the cells of the immune system; particularly in dendritic cell maturation and function. This multifaceted involvement in drug disposition, cancer drug resistance and regulation of the immune response makes P-glycoprotein an attractive target for the optimization of oral anticancer drug treatment strategies. This review introduces and discusses for the first time the potential impact that oral anticancer drugs may have on P-glycoprotein expression and function and the potential consequences of this on dendritic cell function in relation to human cancer. This review also aims to foster a better understanding of the host mediated immunological mechanisms which may be potentially manipulated in cancer patients undergoing oral chemotherapy.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Administration, Oral; Animals; Antineoplastic Agents; Drug Delivery Systems; Drug Resistance, Neoplasm; Humans; Mouth Neoplasms
PubMed: 18288943
DOI: 10.2174/156800908783497168 -
Journal of Bioenergetics and... Feb 1995The overexpression of the P-glycoprotein, the MDR1 gene product, has been linked to the development of resistance to multiple cytotoxic natural product anticancer drugs... (Review)
Review
The overexpression of the P-glycoprotein, the MDR1 gene product, has been linked to the development of resistance to multiple cytotoxic natural product anticancer drugs in certain cancers and cell lines derived from tumors. P-glycoprotein, a member of the ATP-binding cassette (ABC) superfamily of transporters, is believed to function as an ATP-dependent drug efflux pump with broad specificity for chemically unrelated hydrophobic compounds. We review here recent studies on the purification and reconstitution of P-glycoprotein to elucidate the mechanism of drug transport. P-glycoprotein from the human carcinoma multidrug resistant cell line, KB-V1, was purified by sequential chromatography on anion exchange followed by a lectin (wheat germ agglutinin) column. Proteoliposomes reconstituted with pure protein exhibited high levels of drug-stimulated ATPase activity as well as ATP-dependent [3H]vinblastine accumulation. Both the ATPase and vinblastine transport activities of the reconstituted P-glycoprotein were inhibited by vanadate. In addition, the vinblastine transport was inhibited by verapamil and daunorubicin. These studies provide strong evidence that the human P-glycoprotein functions as an ATP-dependent drug transporter. The development of the reconstitution system and the availability of recombinant protein in large amounts due to recent advances in overexpression of P-glycoprotein in a heterologous expression system should facilitate a better understanding of the function of this novel protein.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adenosine Triphosphatases; Biological Transport; Drug Resistance, Multiple; Humans; KB Cells; Liposomes; Proteolipids; Vinblastine
PubMed: 7629047
DOI: 10.1007/BF02110327