RT Journal Article
SR Electronic
T1 RPR112378 and RPR115781: Two Representatives of a New Family of Microtubule Assembly Inhibitors
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 553
OP 563
DO 10.1124/mol.57.3.553
VO 57
IS 3
A1 Cécile Combeau
A1 Jean Provost
A1 Frédérique Lancelin
A1 Yann Tournoux
A1 François Prod'homme
A1 Frédéric Herman
A1 François Lavelle
A1 Jean Leboul
A1 Marc Vuilhorgne
YR 2000
UL http://molpharm.aspetjournals.org/content/57/3/553.abstract
AB 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 (IC50 = 1.2 μM) 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.