title: Demethyl fruticulin A (SCO-1) causes apoptosis by inducing reactive oxygen species in mitochondria.
abstract: Demethyl fruticulin A (SCO-1) is a compound found in Salvia corrugata leaves. SCO-1 was reported to induce anoikis in cell lines via the membrane scavenging receptor CD36. However, experiments performed with cells lacking CD36 showed that SCO-1 was able to induce apoptosis also via alternative pathways. To gain some insight into the biological processes elicited by this compound, we undertook an unbiased genomic approach. Upon exposure of glioblastoma tumor initiating cells (GBM TICs) to SCO-1 for 24 h, we observed a deregulation of the genes belonging to the glutathione metabolism pathway and of those belonging to the biological processes related to the response to stress and to chemical stimulus. On this basis, we hypothesized that the SCO-1 killing effect could result from the induction of reactive oxygen species (ROS) in the mitochondria. This hypothesis was confirmed by flow cytometry using MitoSOX, a mitochondria-selective fluorescent reporter of ROS, and by the ability of N-acetyl cysteine (NAC) to inhibit apoptosis when co-administered with SOC-1 to the GBM TICs. We further show that NAC also protects other cell types such as HeLa, MG-63, and COS-7 from apoptosis. We therefore propose that ROS production is the major molecular mechanism responsible for the pro-apoptotic effect induced by SCO-1. Consequently, SCO-1 may have a potential therapeutic value, which deserves further investigation in animal models.
authors.affiliation: Centro Biotecnologie Avanzate, Genova, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Monticone
authors.forename: Angela
authors.initials: A
authors.lastname: Bisio
authors.forename: Antonio
authors.initials: A
authors.lastname: Daga
authors.forename: Paolo
authors.initials: P
authors.lastname: Giannoni
authors.forename: Walter
authors.initials: W
authors.lastname: Giaretti
authors.forename: Massimo
authors.initials: M
authors.lastname: Maffei
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pfeffer
authors.forename: Francesco
authors.initials: F
authors.lastname: Romeo
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Quarto
authors.forename: Giovanni
authors.initials: G
authors.lastname: Romussi
authors.forename: Giorgio
authors.initials: G
authors.lastname: Corte
authors.forename: Patrizio
authors.initials: P
authors.lastname: Castagnola
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology*; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D005978:Glutathione / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D017382:Reactive Oxygen Species; C539555:demethylfruticuline A; D005978:Glutathione