11,13-dihydro-dehydroleucodine, a derivative of dehydroleucodine with an inactivated alkylating function conserves the anti-proliferative activity in G2 but does not cause cytotoxicity.
Modulation of vascular smooth muscle cell (VSMC) proliferation has critical therapeutic implications for vascular disease. Recently, we demonstrated 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 or factors involved in key biological processes. We analyzed whether the DhL alpha-methylene-gamma-lactone function is directly involved in cell proliferation arrest in G2 and in cell toxicity. To this end, the effects of both DhL and 11,13-dihydro-dehydroleucodine (2H-DhL), a derivative of DhL with inactivated alpha-methylenelactone function, on cultured VSMC viability and proliferation were assessed. We found that both DhL and 2H-DhL inhibited the proliferation of VSMCs in a dose-dependent manner, inducing a transient arrest in G2 phase. DhL, but not 2H-DhL, had a cytotoxic effect at concentrations up to 12 microM, 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.
Polo
Luis M
LM
Laboratory of Cell Cycle and Cytoskeleton, IHEM, Facultad de Ciencias Medicas, Universidad Nacional de Cuyo, Argentina.
Castro
Claudia M
CM
Cruzado
Montserrat C
MC
Collino
César J G
CJ
Cuello-Carrión
F Darío
FD
Ciocca
Daniel R
DR
Giordano
Oscar S
OS
Ferrari
Monica
M
López
Luis A
LA
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D016195:G2 Phase; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011921:Rats, Inbred WKY; D012717:Sesquiterpenes / Q000494:pharmacology*
C518543:11,13-dihydro-dehydroleucodine; D007783:Lactones; D012717:Sesquiterpenes; C079949:dehydroleucodine