Preface: the concept and consequences of multidrug resistance

Abstract

The problem of multidrug resistance (MDR) in human cancers led to the discovery 30 years ago of a single protein P-glycoprotein (P-gp), capable of mediating resistance to multiple structurally diverse drugs. P-gp became the archetypal eukaryotic ABC transporter gene, and studies of P-gp and related ABC transporters in both eukaryotes and bacteria have led to a basic mechanistic understanding of the molecular basis of MDR. Particular milestones along the way have been the identification of the homology between P-gp and bacterial transport proteins, the purification and functional reconstitution of P-gp into synthetic lipid systems, and the development of targeted therapies that attempt to overcome MDR by inhibiting Pgp. This preface places into this context some of the less well-explored themes developed in the MDR field, particularly various alternative models of P-gp action, evidence for parallel physiological roles for P-gp, and the unusual relationship between the substrate recognition capabilities of ABC transporters and their evolutionary history.

Novel structure–activity relationships and selectivity profiling of cage dimeric 1,4-dihydropyridines as multidrug resistance (MDR) modulators

“…2,10,11 Most important problems in the clinical application of such inhibitors have been massive side effects and drug interactions which strongly limit their usage so far. 12,13 The undesired side effects mainly result from a nonselective inhibition of the different naturally occurring efflux pumps by such inhibitors. 14 Most inhibitors affect not only a desired tumour-cell relevant overexpressed efflux pump but also other structurally related ones which protect normal cells from toxification.…”

Multiple Drug Resistance Proteins of Pulmonary Somatic Cells and Their Specific Expression in Fibrous Cavernous Tuberculosis

“…В настоящее время сформировано научное направление, которое убедительно показало, что в результате воздействия на опухолевые клетки ле карственными препаратами запускаются механиз мы, приводящие к развитию множественной лекар ственной устойчивости (М ЛУ) опухолевых клеток разного гистогенеза [2,12]. Механизмы МЛУ реа лизуются в первую очередь работой специальных транспортных белков, локализующихся преиму щественно на плазматической мембране и функци онирующих в качестве «насосов», использующих для своей активности энергию АТФ [1,5,17]. В ре зультате работы таких белков происходит снижение внутриклеточного накопления препаратов за счет их выведения из цитоплазмы во внеклеточную среду.…”

Evidence for Time-Dependent Interactions between Ritonavir and Lopinavir/Ritonavir Plasma Levels Following P-Glycoprotein Inhibition in Sprague-Dawley Rats

“…8) P-gp is an ATP-dependant membrane transporter with broad substrate specificity, capable of mediating efflux of a variety of structurally diverse drugs. 9) There is a strong suggestion that different binding sites exist on the P-gp transporter, 10,11) while there is also evidence of competitive and non-competitive inhibition of these sites. 11) P-gp is expressed in a multitude of organs such as the liver, intestinal epithelial cells, kidney and blood-brain barrier in both humans and rodents.…”

“…A number of studies in the literature have investigated the possibility that variation in P-gp expression may have an impact on treatment outcomes of highly active antiretroviral therapy (HAART). 20,21) To further illustrate the important contribution of P-gp to treatment response, an earlier study in rats by Usansky et al 22) found that the absorption of saquinavir was increased 20-fold when the expression of P-gp was inhibited. Furthermore, the authors also found that the inter-individual variability of saquinavir decreased following the inhibition of P-gp.…”