New Natural Sesquiterpenes as Modulators of Daunomycin Resistance in a Multidrug-Resistant Leishmania tropica Line,

Pérez‐Victoria, José M.; Tincusi, Benigna M.; Jiménez, Ignacio A.; Bazzocchi, Isabel L.; Gupta, Mahabir P.; Castanys, Santiago; Gamarro, Francisco; Ravelo, Ángel G.

doi:10.1021/jm991066b

Cited by 62 publications

(74 citation statements)

References 29 publications

(95 reference statements)

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“…Among the active compounds identified in those extracts are sesquiterpenes, which constitute a wide family of natural compounds with a considerable range of bioactive properties and with potential clinical applications as anticancer drugs, and MDR reversal agents in cancer cells (16) and in the protozoan parasite Leishmania (17,18). Because of these previous findings, we have initiated research to determine the cellular target(s) for sesquiterpenes and to characterize their molecular mechanism of action to rationally design new, more efficient modulators based on their chemical structure.…”

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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“…Hasta ahora, se han establecido varios grupos químicos que, al parecer, inhiben la función de la Pgp al competir con algunos medicamentos por la unión a dicha glicoproteína en el dominio TM que participa directamente en el transporte del medicamento o por la unión al sitio de fijación del nucleótido conocida como región NBD y, de esta forma, evitan que los medicamentos sean finalmente expulsados mediante la proteína de eflujo Pgp. ocurría por la fijación de los compuestos al dominio TM de la Pgp y no a la región NBD, al menos, en el bloqueo del eflujo de daunomicina (139).…”

Section: Moduladores De Pgp En Leishmania Sppunclassified

Leishmania: papel de la glicoproteína P en la mediación de resistencia a medicamentos y estrategias de reversión.

et al. 2005

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Actualmente, los parásitos protozoarios son uno de los principales agentes causantes de morbilidad y mortalidad en el mundo, un problema complicado, además, por la aparición de resistencia a medicamentos en estos organismos. La resistencia a medicamentos observada en parásitos protozoarios se debe a diferentes mecanismos como la disminución de la entrada del medicamento a la célula por cambios en el transportador requerido, la pérdida de la activación del medicamento por parte del hospedero, las alteraciones en el blanco del medicamento y la expresión exagerada del transportador múltiple de medicamentos o glicoproteína P (Pgp). En esta revisión, nos centramos en: 1) el papel de las glicoproteínas P (Pgp) de la familia de proteínas ABC (ATP binding cassette) como los transportadores de múltiples medicamentos en la mediación de resistencia en protozoarios, especialmente en Leishmania, y en el desarrollo de resistencia cruzada para medicamentos estructural y funcionalmente no relacionados, y 2) en algunos conceptos relacionados con los mecanismos moduladores que podrían revertir la resistencia a medicamentos por fármacos y productos naturales. Numerosos moduladores o quimiosensibilizadores son conocidos por alterar la capacidad de las glicoproteínas P para mantener concentraciones intracelulares subtóxicas del medicamento; algunos ejemplos incluyen los bloqueadores de los canales de calcio como el verapamilo; sin embargo, se requieren altas concentraciones para una inhibición eficiente y duradera, las cuales producen efectos adversos indeseables. Por tanto, se necesitan más investigaciones relacionadas con los moduladores naturales para Pgp, los cuales podrían presentar menor toxicidad para el hospedero.Palabras clave: Leishmania, protozoos, multirresistencia, glicoproteína P, productos naturales. Leishmania: role of P glycoprotein in drug resistance and reversion strategiesProtozoan parasites are important causative agents of morbidity and mortality throughout the world -a problem further complicated by the emergence of drug resistance in these parasites. Mechanisms of drug resistance include the following: decreased uptake of the drug into the cell, loss of drug activation, alterations in the drug target, and over-expression of a well-known multiple drug transporter proteins. In this review, two critical components of resistance are stressed: (1) the role of ATP binding cassette proteins, such as P-glycoproteins, in mediating drug resistance in Leishmania and other protozoans, followed by development of cross-resistance to many structurally and functionally unrelated drugs, and (2) some concepts concerning the reversal mechanism of multidrug resistance by drugs and natural products. Several modulators or chemosensitizers alter the capacity of P-glycoproteins to maintain subtoxic intracellular drug concentrations. Calcium channel blockers such as verapamil act in this mode; however, high concentrations are required for an efficient and effective inhibition and, in addition, produce undesirable side effects. The di...

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“…HSQC and HMBC data further supported the assignment of the benzoate group (Supplemental Table 1). The existence of a 2,3-disubstituted pyridine unit was suggested by the signals for three aromatic protons at δ H 8.82 (dd, J = 4.6, 1.9 Hz, H-6 ), 8.39 (dd, J = 8.0, 1.9 Hz, H-4 ), 7.26 (dd, J = 8.0, 4.6 Hz, H-5 ), as well as five aromatic carbons at δ C 168.1 (C-2 ), 153.8 (C-6 ), 138.2 (C-4 ), 124.9 (C-3 ), and 120.8 (C-5 ). HSQC and HMBC data further supported the assignment of the 2,3-disubstituted pyridine unit (Supplemental Table 1).…”

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confidence: 99%

Oppositines A and B, Sesquiterpene Pyridine Alkaloids from a Sri Lankan Pleurostylia opposita

et al. 2006

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Two new sesquiterpene pyridine alkaloids, oppositines A (1) and B (2), have been isolated from the plant, Pleurostylia opposita (Celastraceae), collected in Sri Lanka. The compounds were isolated and purified by solvent/solvent partitioning, column chromatography and HPLC. Their structures were assigned on the basis of extensive 1D and 2D NMR studies as well as analysis by HRESIMS. Oppositines A (1) and B (2) showed moderate cytotoxicity against HCT116 cell lines with EC 50 values of 27 ± 2 and 26 ± 3 μM, respectively.Poly-acetylated sesquiterpene pyridine alkaloids are ubiquitously found in the Celastraceae family of plants. 1-4 Dihydro-β-agarofuran sesquiterpenes frequently incorporate pyridine dicarboxylic acids to bridge their sesquiterpenoid cores at the C-3 and C-13 positions. The dihydro-β-agarofuran skeleton is comprised of a decalin ring, a tetrahydrofuran ring, and methyl substituents located at the C-4, C-10, and two at the C-11 position. Evoninic, wilfordic, edulic, cathaic, and cassininic (often misnamed cassinic) acids are some of the pyridine carboxylic acids present in this class of sesquiterpenes. These compounds are of interest due to their wide range of biological activities including: cytotoxicity, 1 immunosuppression, 2 insecticidal, 3,5,6 insect-antifeedant, 5,7 anti-HIV, 4 reversal of the multidrug resistance (MDR) phenotype, 8-11 and antitumor. 12 As part of an ongoing search for bioactive compounds, two new sesquiterpene alkaloids, oppositines A (1) and B (2), were isolated from the Sri Lankan plant, Pleurostylia opposita (Wallich, 1824) (Celastraceae).The air dried stem bark of P. opposita was extracted with 1:1 MeOH/CH 2 Cl 2 . The extract was dried and partitioned between petroleum ether and aqueous MeOH, and the aqueous MeOH was subsequently partitioned with chloroform. The chloroform-soluble material was fractionated using size exclusion chromatography, preparative TLC, and reversed-phase HPLC resulting in oppositines A (1) and B (2).

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New Natural Sesquiterpenes as Modulators of Daunomycin Resistance in a Multidrug-Resistant Leishmania tropica Line^,

Cited by 62 publications

References 29 publications

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

Leishmania: papel de la glicoproteína P en la mediación de resistencia a medicamentos y estrategias de reversión.

Oppositines A and B, Sesquiterpene Pyridine Alkaloids from a Sri Lankan Pleurostylia opposita

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