Multidrug Resistance Reversal Agents

Robert, Jacques; Jarry, Christian

doi:10.1002/chin.200406259

Cited by 40 publications

(57 citation statements)

References 1 publication

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“…Third-generation modulators that specifically and potently inhibit P-glycoprotein have been developed to overcome the limitations of the previous ones (8,14). Although the preliminary results of ongoing clinical trials are hopeful, their efficacy in cancer patients has not yet been shown (15). Therefore, in anticipation of a possible clinical failure of the third-generation modulators currently under study or to complement them in case of success, it is still necessary to search for new, efficient P-glycoprotein modulators without undesirable side effects.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…Since MDR mediated by Pgp has been documented in a variety of human cancer cells and in same case, such as in some carcinomas including breast, ovarian, and renal, has been shown to be associated with a poor response to cancer chemotherapy, [7][8][9][10][11][12][13][14][15][16] UFH could be used as chemosensitizer in the clinical setting to inhibit the mechanism of pleiotropic chemoresistance Pgp-mediated and to potentiate chemotherapy. 17,18 In this study, we evaluated the in vitro effects of UFH on the Pgp function and activity using a human breast cancer cell line, such as MDA-MB-231 19 and assessed whether these effects increased the sensitivity of this carcinoma cell type to antineoplastic drugs. The functional ability of Pgp was tested by measuring intracellular retention of the MDR Pgp-mediated marker, calcein acetoxymethylester (calcein-AM).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of P-glycoprotein-mediated multidrug resistance by unfractionated heparin: A new potential chemosensitizer for cancer therapy

Angelini

Febbo²,

Ciofani³

et al. 2005

Cancer Biology & Therapy

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“…[4][5][6] An obstacle in applying classical MDR modulators arises from their commonly occurring intrinsic toxicity at doses necessary to be active, for example, heart failure, hypotension, hyperbilirubinemia, and immunosuppression by cyclosporin A. Moreover, improved so-called second-generation MDR modulators were demonstrated to induce enhanced activity of liver enzymes of the family of cytochrome P450 mixed-function oxidases resulting in an increased pharmacokinetic turn over of the applied anticancer drugs.…”

mentioning

confidence: 99%

Stable and complete overcoming of MDR1/P-glycoprotein-mediated multidrug resistance in human gastric carcinoma cells by RNA interference

et al. 2004

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Multidrug resistance (MDR) is the major cause of failure of effective chemotherapeutic treatment of disseminated neoplasms. The ''classical'' MDR phenotype of human malignancies is mediated by drug extrusion by the adenosine triphosphate binding cassette (ABC)-transporter P-glycoprotein (MDR1/P-gp). For stable reversal of ''classical'' MDR by RNA interference (RNAi) technology, an H1-RNA gene promoter-driven expression vector encoding anti-MDR1/P-gp short hairpin RNA (shRNA) molecules was constructed. By introduction of anti-MDR1/P-gp shRNA expression vectors into the extremely high drug-resistant human gastric carcinoma cell line EPG85-257RDB, the MDR phenotype was completely reversed. The reversal of MDR was accompanied by a complete suppression of MDR1/P-gp expression on mRNA and protein level, and by a considerable increased intracellular anthracyline accumulation in the anti-MDR1/P-gp shRNA-treated cells. The data indicate that stable shRNA-mediated RNAi can be tremendously effective in reversing MDR1/P-gp-mediated MDR and is therefore a promising strategy for overcoming MDR by gene therapeutic applications.

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Multidrug Resistance Reversal Agents

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 40 publications

References 1 publication

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

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

Inhibition of P-glycoprotein-mediated multidrug resistance by unfractionated heparin: A new potential chemosensitizer for cancer therapy

Stable and complete overcoming of MDR1/P-glycoprotein-mediated multidrug resistance in human gastric carcinoma cells by RNA interference

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