Modulation of P‐glycoprotein‐mediated multidrug resistance by acceleration of passive drug permeation across the plasma membrane

Regev, Ronit; Katzir, Hagar; Yeheskely‐Hayon, Daniella; Eytan, Gera D.

doi:10.1111/j.1742-4658.2007.06140.x

Cited by 47 publications

(32 citation statements)

References 38 publications

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“…Many aspects of our findings on effectiveness agree with previous work (Eytan et al, 1996b;Eytan et al, 1997;Regev et al, 2007;Tran et al, 2005;von Richter et al, 2009) reporting that the passive flux of a substrate, i.e. the rate of permeation into and across the plasma membrane, is the major factor governing transport effectiveness.…”

Section: Transport Effectiveness and Substrate Fluxsupporting

confidence: 91%

Cost, effectiveness and environmental relevance of multidrug transporters in sea urchin embryos

Cole

Hamdoun

Epel

2013

Journal of Experimental Biology

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SUMMARY ATP-binding cassette transporters protect cells via efflux of xenobiotics and endogenous byproducts of detoxification. While the cost of this ATP-dependent extrusion is known at the molecular level, i.e. the ATP used for each efflux event, the overall cost to a cell or organism of operating this defense is unclear, especially as the cost of efflux changes depending on environmental conditions. During prolonged exposure to xenobiotics, multidrug transporter activity could be costly and ineffective because effluxed substrate molecules are not modified in the process and could thus undergo repeated cycles of efflux and re-entry. Here we use embryos of the purple sea urchin, Strongylocentrotus purpuratus, as a model to determine transport costs and benefits under environmentally relevant xenobiotic concentrations. Strikingly, our results show that efflux transporter activity costs less than 0.2% of total ATP usage, as a proportion of oxygen consumption. The benefits of transport, defined as the reduction in substrate accumulation due to transporter activity, depended largely, but not entirely, on the rate of passive flux of each substrate across the plasma membrane. One of the substrates tested exhibited rapid membrane permeation coupled with high rates of efflux, thus inducing rapid and futile cycles of efflux followed by re-entry of the substrate. This combination significantly reduced transporter effectiveness as a defense and increased costs even at relatively low substrate concentrations. Despite these effects with certain substrates, our results show that efflux transporters are a remarkably effective and low-cost first line of defense against exposure to environmentally relevant concentrations of xenobiotics.

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Section: Transport Effectiveness and Substrate Fluxsupporting

confidence: 91%

Cost, effectiveness and environmental relevance of multidrug transporters in sea urchin embryos

Cole

Hamdoun

Epel

2013

Journal of Experimental Biology

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“…Drug concentration inside the MDR cells is the outcome of competition between the active export of drugs by drug efflux pumps, such as P-gp, and the passive permeation of drugs across the plasma membrane [27] .…”

Section: Discussionmentioning

confidence: 99%

Synergistic effect of hyperthermia and neferine on reverse multidrug resistance in adriamycin-resistant SGC7901/ADM gastric cancer cells

Huang

Cao

et al. 2011

J. Huazhong Univ. Sci. Technol. [Med. Sci.]

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Multidrug resistance (MDR) plays a major obstacle to successful gastric cancer chemotherapy. The purpose of this study was to investigate the MDR reversal effect and mechanisms of hyperthermia in combination with neferine (Nef) in adriamycin (ADM) resistant human SGC7901/ADM gastric cancer cells. The MDR cells were heated at 42°C and 45°C for 30 min alone or combined with 10 μg/mL Nef. The cytotoxic effect of ADM was evaluated by MTT assay. Cellular plasma membrane lipid fluidity was detected by fluorescence polarization technique. Intracellular accumulation of ADM was monitored with high performance liquid chromatography. Mdr-1 mRNA, P-glycoprotein (P-gp), γH2AX expression and γH2AX foci formation were determined by real-time PCR, Western blot and immunocytochemical staining respectively. It was found that different heating methods induced different cytotoxic effects. Water submerged hyperthermia had the strongest cytotoxicity of ADM and Nef combined with hyperthermia had a synergistic cytotoxicity of ADM in the MDR cells. The water submerged hyperthermia increased the cell membrane fluidity. Both water submerged hyperthermia and Nef increased the intracellular accumulation of ADM. The water submerged hyperthermia and Nef down-regulated the expression of mdr-1 mRNA and P-gp. The water submerged hyperthermia could damage DNA and increase the γH2AX expression of SGC7901/ADM cells. The higher temperature was, the worse effect was. Our results show that combined treatment of hyperthermia with Nef can synergistically reverse MDR in human SGC7901/ADM gastric cancer cells.

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“…Transport inhibition does not appear to involve direct interaction between these agents and Pgp, and is probably linked to increases in membrane fluidity or permeability (146, 147). …”

Section: Modulation Of Pgp Functions By the Membranementioning

confidence: 99%

Complex Interplay between the P-Glycoprotein Multidrug Efflux Pump and the Membrane: Its Role in Modulating Protein Function

2014

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Multidrug resistance in cancer is linked to expression of the P-glycoprotein multidrug transporter (Pgp, ABCB1), which exports many structurally diverse compounds from cells. Substrates first partition into the bilayer and then interact with a large flexible binding pocket within the transporter’s transmembrane regions. Pgp has been described as a hydrophobic vacuum cleaner or an outwardly directed drug/lipid flippase. Recent X-ray crystal structures have shed some light on the nature of the drug-binding pocket and suggested routes by which substrates can enter it from the membrane. Detergents have profound effects on Pgp function, and several appear to be substrates. Biochemical and biophysical studies in vitro, some using purified reconstituted protein, have explored the effects of the membrane environment. They have demonstrated that Pgp is involved in a complex relationship with its lipid environment, which modulates the behavior of its substrates, as well as various functions of the protein, including ATP hydrolysis, drug binding, and drug transport. Membrane lipid composition and fluidity, phospholipid headgroup and acyl chain length all influence Pgp function. Recent studies focusing on thermodynamics and kinetics have revealed some important principles governing Pgp–lipid and substrate–lipid interactions, and how these affect drug-binding and transport. In some cells, Pgp is associated with cholesterol-rich microdomains, which may modulate its functions. The relationship between Pgp and cholesterol remains an open question; however, it clearly affects several aspects of its function in addition to substrate–membrane partitioning. The action of Pgp modulators appears to depend on their membrane permeability, and membrane fluidizers and surfactants reverse drug resistance, likely via an indirect mechanism. A detailed understanding of how the membrane affects Pgp substrates and Pgp’s catalytic cycle may lead to new strategies to combat clinical drug resistance.

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Modulation of P‐glycoprotein‐mediated multidrug resistance by acceleration of passive drug permeation across the plasma membrane

Cited by 47 publications

References 38 publications

Cost, effectiveness and environmental relevance of multidrug transporters in sea urchin embryos

Cost, effectiveness and environmental relevance of multidrug transporters in sea urchin embryos

Synergistic effect of hyperthermia and neferine on reverse multidrug resistance in adriamycin-resistant SGC7901/ADM gastric cancer cells

Complex Interplay between the P-Glycoprotein Multidrug Efflux Pump and the Membrane: Its Role in Modulating Protein Function

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