P-glycoprotein as a therapeutic target: good news

Shtil, Alexander А.

doi:10.1038/sj.leu.2402664

Cited by 4 publications

(2 citation statements)

References 8 publications

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“…It is also worth noting that the most efficient sesquiterpenes were less toxic than verapamil toward cultured drug-sensitive cells but were specifically more toxic toward P-glycoprotein-expressing cells (data not shown). This finding is very interesting, considering that P-glycoprotein is presumably involved in malignancy of cancer cells as well as drug resistance (41) and that inhibition of P-glycoprotein by PSC-833 led to a selective direct elimination of MDR cells (42).…”

Section: Discussionmentioning

confidence: 89%

Celastraceae Sesquiterpenes as a New Class of Modulators That Bind Specifically to Human P-Glycoprotein and Reverse Cellular Multidrug Resistance

Muñoz-Martínez

Cortés-Selva

et al. 2004

Cancer Research

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Overexpression of ABCB1 (MDR1) P-glycoprotein, a multidrug efflux pump, is one mechanism by which tumor cells may develop multidrug resistance (MDR), preventing the successful chemotherapeutic treatment of cancer. Sesquiterpenes from Celastraceae family are natural compounds shown previously to reverse MDR in several human cancer cell lines and Leishmania strains. However, their molecular mechanism of reversion has not been characterized. In the present work, we have studied the ability of 28 dihydro-␤-agarofuran sesquiterpenes to reverse the P-glycoprotein-dependent MDR phenotype and elucidated their molecular mechanism of action. Cytotoxicity assays using human MDR1-transfected NIH-3T3 cells allowed us to select the most potent sesquiterpenes reversing the in vitro resistance to daunomycin and vinblastine. Flow cytometry experiments showed that the above active compounds specifically inhibited drug transport activity of P-glycoprotein in a saturable, concentration-dependent manner (K i down to 0.24 ؎ 0.01 mol/L) but not that of ABCC1 (multidrug resistance protein 1; MRP1), ABCC2 (MRP2), and ABCG2 (breast cancer resistance protein; BCRP) transporters. Moreover, sesquiterpenes inhibited at submicromolar concentrations the P-glycoprotein-mediated transport of [ 3 H]colchicine and tetramethylrosamine in plasma membrane from CH R B30 cells and P-glycoproteinenriched proteoliposomes, supporting that P-glycoprotein is their molecular target. Photoaffinity labeling in plasma membrane and fluorescence spectroscopy experiments with purified protein suggested that sesquiterpenes interact with transmembrane domains of P-glycoprotein. Finally, sesquiterpenes modulated P-glycoprotein ATPase-activity in a biphasic, concentration-dependent manner: they stimulated at very low concentrations but inhibited ATPase activity as noncompetitive inhibitors at higher concentrations. Sesquiterpenes from Celastraceae are promising P-glycoprotein modulators with potential applications in cancer chemotherapy because of their MDR reversal potency and specificity for P-glycoprotein.

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Section: Discussionmentioning

confidence: 89%

Celastraceae Sesquiterpenes as a New Class of Modulators That Bind Specifically to Human P-Glycoprotein and Reverse Cellular Multidrug Resistance

Muñoz-Martínez

Cortés-Selva

et al. 2004

Cancer Research

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“…Among the various formulations of liposomal anthracyclines that have been studied and even marketed, none appears able to recruit responders outside the usual field of anthracycline activity. Finally, a very recent optimistic note is worth a mention: 132 Lehne et al 133 have shown in vivo that the simple inhibition of P-glycoprotein by valspodar may lead to the direct elimination of MDR cells perhaps because this membrane pump is also involved in malignancy as well as in drug resistance. This observation warrants further exploration, and a careful reexamination of the clinical trials already performed may shed some light upon this.…”

Section: Perspectivementioning

confidence: 99%