11,13-dihydro-dehydroleucodine, a derivative of dehydroleucodine with an

POLO, LM; CASTRO, CM; CRUZADO, MC; COLLINO, CJG; CUELLO-CARRIÓN, FD; CIOCCA, DR; GIORDANO, OS; FERRARI, M; LÓPEZ, LA

EUROPEAN JOURNAL OF PHARMACOLOGY

ELSEVIER

Año: 2007 vol. 556 p. 19 - 26

0014-2999

Modulation of vascular smooth muscle cell (VSMC) proliferation has critical therapeutic implications for vascular disease. Recently, wedemonstrated that the sesquiterpene lactone dehydroleucodine (DhL) inhibited the proliferation of VSMCs in G2 phase. It is known that the alpha,beta-unsaturated carbonyl group of the sesquiterpene lactone has a nonspecific alkylating activity that inhibits a large number of enzymes orfactors involved in key biological processes. We analyzed whether the DhL alpha-methylene-gamma-lactone function is directly involved in cellproliferation arrest in G2 and in cell toxicity. To this end, the effects of both DhL and 11,13-dihydro-dehydroleucodine (2H-DhL), a derivative ofDhL with inactivated alpha-methylenelactone function, on cultured VSMC viability and proliferation were assessed. We found that both DhL and2H-DhL inhibited the proliferation of VSMCs in a dose-dependent manner, inducing a transient arrest in G2 phase. DhL, but not 2H-DhL, had acytotoxic effect at concentrations up to 12 μM, indicating that cell proliferation arrest and cytotoxicity are mediated by different cellular targets.From these results we infer that only 2H-DhL is able to arrest cell proliferation in G2 without affecting cell viability at any concentration.© 2006 Elsevier B.V. All rights reserved.