Apoptosis induction and modulation of P-glycoprotein mediated multidrug resistance by new macrocyclic lathyrane-type diterpenoids |
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Authors: | Duarte Noélia Varga Andras Cherepnev Georg Radics Rita Molnár Joseph Ferreira Maria-José U |
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Institution: | 1. CECF, Faculty of Pharmacy, University of Lisbon, Av. das Forças Armadas, 1600-083 Lisbon, Portugal;2. Department of Molecular Parasitology, Humboldt University, D-10115 Berlin, Germany;3. Medical Immunology (Charité), Humboldt University, D-10115 Berlin, Germany;4. Department of Medical Microbiology and Immunobiology, University of Szeged, H-6720 Szeged, Hungary |
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Abstract: | The macrocyclic lathyrane diterpenes, latilagascenes D-F (1-3) and jolkinol B (4), were isolated from the methanol extract of Euphorbia lagascae, and evaluated for multidrug resistance reversing activity on mouse lymphoma cells. All compounds displayed very strong activity compared with that of the positive control, verapamil. The structure-activity relationship is discussed. The evaluation of compounds 1 and 4, and of latigascenes A-C (5-7), isolated from the same species, as apoptosis-inducers was also carried out. Compound 1 was the most active. Furthermore, in the model of combination chemotherapy, the interaction between the doxorubicine and latilagascene B (6) was studied in vitro, on human MDR1 gene transfected mouse lymphoma cells, showing that the type of interaction was synergistic. Latilagascenes D-F (1-3) are new compounds whose structures were established on the basis of spectroscopic methods, including 2D NMR experiments (COSY, HMQC, HMBC and NOESY). |
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