Calcium ionophoretic and apoptotic effects of ferutinin in the human Jurkat T-cell line.
We have investigated the ionophoretic and apoptotic properties of the daucane sesquiterpene ferutinin and three related compounds, ferutidin, 2-alpha-hydroxyferutidin and teferin, all isolated from various species of plants from the genus Ferula. Ferutinin induced a biphasic elevation of intracellular Ca2+ in the leukemia T-cell line, Jurkat. First, a rapid calcium peak was observed and inhibited by BAPTA-AM. This initial calcium mobilization was followed by a sustained elevation, mediated by the entry of extracellular calcium through L-type calcium channels and sensitive to inhibition by EGTA. Moreover, ferutinin-induced apoptosis in Jurkat cells, and this event was preceded, in a cyclosporine-A sensitive manner, by a loss of mitochondrial transmembrane potential (DeltaPsim) and by an increase in intracellular reactive oxygen species. Ferutinin-induced DNA fragmentation was mediated by a caspase-3-dependent pathway, and was initiated independently of any specific phase of the cell cycle. The evaluation of ferutinin analogs in calcium mobilization and apoptosis assays showed strict structure-activity relationships, with p-hydroxylation of the benzoyl moiety being requested for activity.
Macho
Antonio
A
Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Facultad de Medicina, Avda. de Menendez Pidal s/n, E-14004 Córdoba, Spain.
Blanco-Molina
Magdalena
M
Spagliardi
Paola
P
Appendino
Giovanni
G
Bremner
Paul
P
Heinrich
Michael
M
Fiebich
Bernd L
BL
Muñoz
Eduardo
E
D017209:Apoptosis; D001565:Benzoates / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds; D002118:Calcium / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003508:Cycloheptanes; D006801:Humans; D019169:Jurkat Cells; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes; D014407:Tumor Cells, Cultured
D001565:Benzoates; D001643:Bridged Bicyclo Compounds; D003508:Cycloheptanes; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; C111068:4-oxy-6-(4-oxybezoyloxy)dauc-8,9-en; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D002118:Calcium