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More than 40 years ago, the observation that doxorubicin-resistant tumor cells were cross-resistant to several structurally different anticancer agents was the first step in the discovery of P-glycoprotein (P-gp). P-gp belongs to the superfamily of ATP-binding cassette (ABC) transporters;its overexpression has become a therapeutic target for overcoming multidrug resistance in tumors. However, P-gp is also expressed in cells of normal tissues where it plays a physiological role, by protecting them from the toxic effects of xenobiotics. Also, ABCB1 gene polymorphisms may influence the response to anticancer drugs substrate of P-gp. Several strategies to overcome P-gp tumor drug resistance have been suggested. P-gp 'circumvention’ is the most explored and is based on the coadministration of anticancer agents and pump inhibitors (P-gp modulators). Despite the positive findings obtained in preclinical studies, results of clinical trials are not yet successful and clinical research is still ongoing. Other investigational approaches have been studied (e.g. P-gp targeting antibodies, use of antisense strategies or transcriptional regulators targeting ABCB1 gene expression) but their use is still circumscribed to the preclinical setting. A further approach is represented by the encapsulation of P-gp substrate anticancer drugs into liposomes or nanoparticles. This strategy has shown higher efficacy in tumor previously treated with the free drug. The reasons explaining the increased efficacy of liposomal/nanoparticle-based drugs in Pgp-overexpressing tumors include the coating with specific surfactants, the composition changes in the plasma membrane microdomains where P-gp is embedded, the direct impairment of P-gp catalytic mechanisms exerted by specific component of the liposomal shell, but are not yet fully understood. A second strategy to overcome P-gp tumor drug resistance is represented by exploiting the P-gp presence. Actually, P-gp-overexpressing cells show increased sensitivity (collateral sensitivity) to some drugs (e.g. verapamil, narcotic analgesics) and to some investigational compounds (e.g. NSC73306). P-gp-overexpressing cell are hypersensitive to reactive oxygen species, to agents perturbing the energetic metabolic pathways, changing the membrane compositions, reducing the efflux of endogenous toxic catabolites. However, the mechanisms explaining collateral sensitivity have not been fully elucidated. Another approach to exploit P-gp is represented by ABCB1 gene transfer to transform bone marrow progenitor cells into a drug resistant state which may allow conventional or higher doses of anticancer drug substrates of P-gp to be administered safely after transplantation. More recently the development and introduction in the clinics of anticancer drugs which are not substrates of P-gp (e.g. new microtubule modulators, topoisomerase inhibitors) has provided a new and promising strategy to overcome P-gp tumor drug resistance (P-gp 'evasion'). This ‘research topic’ issue aims at exploding the above mentioned matters, in particular by: -retracing the history of the first researches on P-gp - describing the physiological role of P-gp - describing the molecular basis, structural features and mechanism of action of P-gp - describing diagnostic laboratory methods useful to determine the expression of P-gp and its transporter function - describing strategies to overcome tumor drug resistance due to P-gp and other ABC transporters - indicating novel approaches to overcome P-gp multidrug resistance, ranging from basic research studies to pre-clinical/clinical studies.

multidrug resistance --- reversing strategies --- P-Glycoprotein --- Cancer

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"P-glycoprotein (P-gp), encoded by the multidrug-resistance (MDR)-1 gene is one of the best studied efflux transporters that is linked to multidrug resistance in cancer chemotherapies. P-gp belongs to the ATP-binding cassette (ABC) transporter family of proteins that utilizes energy derived from hydrolysis of ATP to efflux endogenous and exogenous xenobiotics, metabolites and toxins from the intracellular space to the outside, thereby providing a general protective role. P-gp is expressed on the apical plasma membrane of all major drug eliminating organs such as the intestine (enterocytes), liver (bile canaliculi), kidney (proximal tubules), brain (endothelia of blood-brain barrier) and in certain tumor types. In the intestine and BBB, P-gp limits entry of drugs by actively pumping drugs back into the lumen or blood, respectively. In the liver and kidney, P-gp actively effluxes drugs, endogenous substances and metabolites into bile or urine, thereby removing them from the body. Upregulation of P-gp in tumor cells is noted in several cancers and is a hallmark for drug resistance. Additionally, P-gp is also shown to play a role in neurogenesis and maintaining homeostasis in the brain. Alteration of P-gp expression is observed in neurodegenerative diseases, highlighting its importance in maintaining normal brain health. Due to its central role in defining oral pharmacokinetics, systemic clearance, tissue exposure, organ health and chemoresistance, much of the research has been focused on modulating P-gp. Chemical inhibitors, formulation-based and epigenetic approaches are applied to modulate P-gp activity with a goal to improve oral pharmacokinetics, increase tumor and brain penetration, minimize organ toxicity and potentially treat neurodegenerative diseases. Although enormous research on P-gp has been published, a book chapter exclusively and comprehensively covering diverse aspects of P-gp, including the recent developments in the field, is required. With much enthusiasm from the publisher, we have collaborated to bring together wide-ranging topics on P-gp. This book contains 12 chapters covering the structure, function, regulation, distribution and expression of P-gp, its pharmacological importance in health and disease and role in pharmacokinetics and drug-drug interactions. Also included are computational approaches to identify selective inhibitors and tactics to modulate P-gp function using chemical inhibitors (synthesized or isolated from marine sources), formulation strategies or epigenetic approaches. The last chapter describes various methods to quantify P-gp expression levels and function in in vitro, in situ and in vivo settings. It is our sincere hope that this material will serve as an important desk reference for students, researchers and clinical scientists in academia, medical research and the pharmaceutical industry working in various fields such as pharmacology, pharmacy, toxicology, medicinal chemistry, pharmaceutical sciences, pharmacokinetics and computational biology"--

Drug resistance in cancer cells. --- P-glycoprotein.

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More than 40 years ago, the observation that doxorubicin-resistant tumor cells were cross-resistant to several structurally different anticancer agents was the first step in the discovery of P-glycoprotein (P-gp). P-gp belongs to the superfamily of ATP-binding cassette (ABC) transporters;its overexpression has become a therapeutic target for overcoming multidrug resistance in tumors. However, P-gp is also expressed in cells of normal tissues where it plays a physiological role, by protecting them from the toxic effects of xenobiotics. Also, ABCB1 gene polymorphisms may influence the response to anticancer drugs substrate of P-gp. Several strategies to overcome P-gp tumor drug resistance have been suggested. P-gp 'circumvention’ is the most explored and is based on the coadministration of anticancer agents and pump inhibitors (P-gp modulators). Despite the positive findings obtained in preclinical studies, results of clinical trials are not yet successful and clinical research is still ongoing. Other investigational approaches have been studied (e.g. P-gp targeting antibodies, use of antisense strategies or transcriptional regulators targeting ABCB1 gene expression) but their use is still circumscribed to the preclinical setting. A further approach is represented by the encapsulation of P-gp substrate anticancer drugs into liposomes or nanoparticles. This strategy has shown higher efficacy in tumor previously treated with the free drug. The reasons explaining the increased efficacy of liposomal/nanoparticle-based drugs in Pgp-overexpressing tumors include the coating with specific surfactants, the composition changes in the plasma membrane microdomains where P-gp is embedded, the direct impairment of P-gp catalytic mechanisms exerted by specific component of the liposomal shell, but are not yet fully understood. A second strategy to overcome P-gp tumor drug resistance is represented by exploiting the P-gp presence. Actually, P-gp-overexpressing cells show increased sensitivity (collateral sensitivity) to some drugs (e.g. verapamil, narcotic analgesics) and to some investigational compounds (e.g. NSC73306). P-gp-overexpressing cell are hypersensitive to reactive oxygen species, to agents perturbing the energetic metabolic pathways, changing the membrane compositions, reducing the efflux of endogenous toxic catabolites. However, the mechanisms explaining collateral sensitivity have not been fully elucidated. Another approach to exploit P-gp is represented by ABCB1 gene transfer to transform bone marrow progenitor cells into a drug resistant state which may allow conventional or higher doses of anticancer drug substrates of P-gp to be administered safely after transplantation. More recently the development and introduction in the clinics of anticancer drugs which are not substrates of P-gp (e.g. new microtubule modulators, topoisomerase inhibitors) has provided a new and promising strategy to overcome P-gp tumor drug resistance (P-gp 'evasion'). This ‘research topic’ issue aims at exploding the above mentioned matters, in particular by: -retracing the history of the first researches on P-gp - describing the physiological role of P-gp - describing the molecular basis, structural features and mechanism of action of P-gp - describing diagnostic laboratory methods useful to determine the expression of P-gp and its transporter function - describing strategies to overcome tumor drug resistance due to P-gp and other ABC transporters - indicating novel approaches to overcome P-gp multidrug resistance, ranging from basic research studies to pre-clinical/clinical studies.

multidrug resistance --- reversing strategies --- P-Glycoprotein --- Cancer

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The book 'Platelet Adhesion to Proteins in Microplates: Applications in Experimental and Clinical Research' by Andreas Eriksson is a medical dissertation from Linköping University. It discusses the crucial role of platelets in preventing blood loss after vessel injury and their role in thrombus formation. The author presents an in-depth analysis of platelet adhesion, their interaction with the extracellular matrix, and their contribution to hemostasis. The book also delves into the potential applications of a platelet adhesion assay in clinical and experimental research. The author's goal is to evaluate the assay's usefulness, particularly in the evaluation of anti-platelet treatments. This book is intended for medical researchers and professionals in the field of pharmacology.

Blood platelets. --- Hemostasis. --- Platelet glycoprotein gpiib-iiia complex. --- Blood platelets --- Hemostasis --- Platelet glycoprotein GPIIb-IIIa complex

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HIV protease inhibitor and non-nucleoside reverse transcriptase inhibitors are important antiretroviral drugs which substantially reduced the morbidity and mortality associated with HIV infection. Recent data have shown relationships between plasma concentrations of these two classes of antiretroviral drug and the clinical response. Therefore, in order to maximise the efficiency and to decrease the toxicity of these drugs, therapeutic drug monitoring appears as a valuate tool.
First, we have developed and validated an analytical method using liquid chromatography coupled with electrospray mass spectrometry (LC-MS/MS) for the simultaneous quantification of 7 antiretroviral agents; five protease inhibitors (atazanavir, saquinavir, lopinavir, ritonavir and tipranavir) and two non-nucleoside reverse transcriptase inhibitors (nevirapine and efavirenz). An analytical run takes 10 minute and the method was validated on a concentration range from 10 to 500 ng/ml. the limits of detection and quantification range from 6.5 to 41.1 ng/ml except for efavirenz and tipranavir, for which these values are somewhat higher.
Second, we tested the implication of the P-glycoprotein (P-gp) in the transmembrane transport of these drugs in order to better understand the great interindividual variations on their pharmacokinetics. This study was performed in two models : in vitro with Caco-2 cells and in vivo in mice deficient for the gene coding for the P-gp. In vitro experiments showed that all tested protease inhibitors are P-gp substrates. Atazanavir seemed to have the greatest functional impact of P-gp genetic polymorphisms. In contrast, non-nucleoside reverse transcriptase inhibitors do not appear to be P-gp substrates. In vivo results are not very conclusive. In vitro results were confirmed in vivo for nevirapine only.
In conclusion, this work provides a sensitive and rapid method for the simultaneous quantification of seven antiretroviral drugs. It open the way for pharmacogenetic investigations over protease inhibitors and more particularly atazanavir Les inhibiteurs de la protéase et les inhibiteurs non-nucléosides de la transcriptase inverse sont d’importants agents antirétroviraux qui ont fortement diminué la morbidité et la mortalité des patients infectés par le virus de l’immunodéficience humaine (VIH). Il a récemment été démontré qu’il existe une relation entre les concentrations plasmatiques de ces agents et le réponse clinique. Le monitoring thérapeutique est dès lors une pratique potentiellement intéressante pour maximiser l’efficacité et diminuer la toxicité de ces deux classes de médicaments.
Dans un premier temps, nous avons mis au point et validé une méthode de dosage par LC-MS/MS (chromatographie liquide à haute performance couplée à un spectromètre de masse en tandem) pour la quantification simultanée de sept antirétroviraux : cinq inhibiteurs de la protéase (atazanavir, saquinavir, lopinavir, ritonavir et tipranavir) et deux inhibiteurs non-nucléosides de la transcriptase inverse (névirapine et éfavirenz). La méthode, dont le temps d’analyse est de 10 minutes, a été validée sur une gamme d’étalonnage allant de 10 à 500 ng/ml. Les limites de détection et de quantification varient de 6.5 à 41.1 ng/ml, sauf pour l’éfavirenz et le tipranavir pour lesquels les valeurs sont un peu plus élevées.
Dans un deuxième temps, dans le but de mieux comprendre l’origine de la grande variabilité interindividuelle dans la pharmacocinétique de ces substance, nous avons testé l’implication éventuelle de la P-glycoprotéine (P-gp) dans leur transport transmembranaire. Cette étude a été réalisée grâce à deux modèles : le modèle in vitro des cellules Caco-2 et le modèle in vivo des souris KO, déficientes pour le gène de la P-gp. Les expériences in vitro ont montré que tous les inhibiteurs de la protéase testés sont substrats de la P-gp. De manière intéressante, il semble que l’atazanavir possède la plus grande affinité pour la protéine de transport et cette substance pourrait donc être utilisée comme modèle à l’avenir pour la protéine de transport et cette substance pourrait donc être utilisée comme modèle à l’avenir pour vérifier l’impact fonctionnel des polymorphismes génétiques de la P-gp. A l’inverse, les inhibiteurs non-nucléosides de la transcriptase inverse ne semblent pas être des substrats de la P-gp. Les résultats des études in vivo sont peu concluants seuls ceux de la névirapine ont confirmé les résultats déjà obtenus par le modèle in vitro.
En conclusion, ce travail offre la possibilité de doser sept agents antirétroviraux aux cours d’une même analyse et ouvre la porte à des investigations de type pharmacogénétique pour les inhibiteurs de la protéase en général et plus particulièrement pour l’atazanavir

Chromatography, Liquid --- Mass Spectrometry --- P-Glycoprotein --- Anti-Retroviral Agents