RPR112378 and RPR115781: Two Representatives of a New Family of Microtubule Assembly Inhibitors
| Autor: | Provost Jean, François Prod'homme, Jean Leboul, Frédéric Herman, Marc Vuilhorgne, Frédérique Lancelin, Yann Tournoux, Cecile Combeau, François Lavelle |
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| Rok vydání: | 2000 |
| Předmět: |
Cell Survival
Chemical structure Size-exclusion chromatography Vinblastine Microtubules KB Cells Magnoliopsida Tubulin Microtubule medicine Humans Binding site Cytotoxicity Pharmacology Binding Sites biology Plant Extracts Tubulin Modulators Sulfhydryl Reagents Antineoplastic Agents Phytogenic Biochemistry Indans biology.protein Molecular Medicine Colchicine HeLa Cells medicine.drug |
| Zdroj: | Molecular Pharmacology. 57:553-563 |
| ISSN: | 1521-0111 0026-895X |
| DOI: | 10.1124/mol.57.3.553 |
| Popis: | A screening program aimed at the discovery of new antimicrotubule agents yielded RPR112378 and RPR115781, two natural compounds extracted from the Indian plant Ottelia alismoides. We report their isolation, structural determination, and mechanisms of action. RPR112378 is an efficient inhibitor of tubulin polymerization (IC(50) = 1.2 microM) and is able to disassemble preformed microtubules. Regarding tubulin activity, RPR115781 is 5-fold less active than RPR112378. Tubulin-RPR112378 complexes, when isolated by gel filtration, were able to block further tubulin addition to growing microtubules, a mechanism that accounts for the substoichiometric effect of the drug. RPR112378 was found to prevent colchicine binding but not vinblastine binding to tubulin. Although colchicine binding is known to induce an increase of tubulin GTPase activity, no such increase was observed with RPR112378. We show that RPR112378 is a highly cytotoxic compound and that RPR115781 is 10, 000-fold less active as an inhibitor of KB cell growth. Part of the cytotoxicity of RPR112378 is probably caused by a reaction of addition with sulfhydryl groups, an observation that has not been made with RPR115781. In conclusion, these molecules represent a new class of inhibitors of microtubule assembly with potential therapeutic value. |
| Databáze: | OpenAIRE |
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