title: Natural daucane esters induces apoptosis in leukaemic cells through ROS production.
abstract: Continuing our research on antiproliferative agents from plants, we extended our interest on further compounds isolated from Ferula communis and Ferulago campestris. One new daucane (DE-20) and one new phenol derivative (PH-3) were isolated and characterized in addition to six daucane, three coumarins and four simple phenolics. The cytotoxic activity was evaluated against a panel of six human tumor cell lines. The derivative DE-17 that resulted moderately active on all the studied cell lines was studied to evaluate its possible mechanism of action. DE-17 was able to induce apoptosis in a time and concentration-dependent manner in SEM and Jurkat cell lines. We observed that DE-17 just after 1h of treatment increased the reactive oxygen species (ROS) production and that the co-incubation of DE-17 with ROS scavengers significantly increased cell viability suggesting that ROS-mediated downstream signaling is essential for the antiproliferative effects of DE-17. At later times of incubation DE-17 induced mitochondrial depolarization, as well as caspase-3 and -9 activation suggesting that apoptosis follow the mitochondrial pathway. Concomitantly to ROS induction, a remarkable decrease of mRNA expression of several antioxidant enzymes and intracellular GSH content was detected in treated cells compared to controls further indicative of oxidative stress. Taken together our results showed for the first time that daucane esters induces apoptotic cell death through a ROS-mediated mechanism in human leukemia cells.
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Padova, Padova, Italy. Electronic address: stefano.dallacqua@unipd.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Dall'Acqua
authors.affiliation: Dipartimento di Salute della Donna e del Bambino - SDB, Laboratorio di Oncoematologia, Università di Padova, Padova, Italy.
authors.forename: Maria Antonella
authors.initials: MA
authors.lastname: Linardi
authors.affiliation: Dipartimento di Salute della Donna e del Bambino - SDB, Laboratorio di Oncoematologia, Università di Padova, Padova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bortolozzi
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Padova, Padova, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Clauser
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Padova, Padova, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Marzocchini
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Camerino, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Maggi
authors.affiliation: Dipartimento di Biologia Ambientale, Università "La Sapienza" Roma, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Nicoletti
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Padova, Padova, Italy.
authors.forename: Gabbriella
authors.initials: G
authors.lastname: Innocenti
authors.affiliation: Dipartimento di Salute della Donna e del Bambino - SDB, Laboratorio di Oncoematologia, Università di Padova, Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: Dipartimento di Salute della Donna e del Bambino - SDB, Laboratorio di Oncoematologia, Università di Padova, Padova, Italy. Electronic address: Giampietro.viola.1@unipd.it.
authors.forename: Giampietro
authors.initials: G
authors.lastname: Viola
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D004952:Esters; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000188:drug therapy; D008928:Mitochondria / Q000378:metabolism; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004952:Esters; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D053148:Caspase 3; D053453:Caspase 9; D005978:Glutathione
keywords: Apoptosis; Coumarins; Daucane sesquiterpenes; Ferula communis; Ferulago campestris; Natural compounds; Reactive oxygen species