title: The isothiocyanate produced from glucomoringin inhibits NF-kB and reduces myeloma growth in nude mice in vivo.
abstract: Glucosinolates (GLs), natural compounds extracted from Brassicaceae and precursors of isothiocyanates (ITCs), have been studied in the last decades mostly due to their chemopreventive activity and, more recently, for their potential use as novel chemotherapeutics. The aim of the present study was to investigate the in vitro and in vivo activity of glucomoringin (GMG), an uncommon member of the GLs family, and to compare it with glucoraphanin (GRA), one of the most studied GL. We have evaluated the potency of both compounds in inducing cell death, cell cycle perturbations, apoptosis, NF-kB inhibition and GST-pi activity in human carcinoma cells with different GST-pi contents as well as in human multiple myeloma and leukaemia cell lines. GMG-derived ITC (GMG-ITC) showed to be more effective compared to GRA-derived ITC (Sulforaphane), especially in inhibiting NF-kB activity and inducing apoptosis through a caspase-dependent pathway; these effects were more pronounced in myeloma cells, in which we could also observe a long lasting growth inhibitory effect, probably due to NF-kB inhibition, which is considered essential for myeloma cell survival. Both GLs were able to induce cell death in the muM range in all tested cell lines but caused cell cycle perturbations only in myeloma cells; they were also able to modulate the GST/GSH pathway by causing a 3-fold increase in GST-pi activity in MCF7 cells. In vivo study showed that pure GMG-ITC was only slightly active in a carcinoma mice model, whereas it had significant antitumoral activity in a myeloma model, causing little toxicity.
authors.affiliation: Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy. brunelli@marionegri.it
authors.forename: Dario
authors.initials: D
authors.lastname: Brunelli
authors.forename: Michele
authors.initials: M
authors.lastname: Tavecchio
authors.forename: Cristiano
authors.initials: C
authors.lastname: Falcioni
authors.forename: Roberta
authors.initials: R
authors.lastname: Frapolli
authors.forename: Eugenio
authors.initials: E
authors.lastname: Erba
authors.forename: Renato
authors.initials: R
authors.lastname: Iori
authors.forename: Patrick
authors.initials: P
authors.lastname: Rollin
authors.forename: Jessica
authors.initials: J
authors.lastname: Barillari
authors.forename: Carla
authors.initials: C
authors.lastname: Manzotti
authors.forename: Paolo
authors.initials: P
authors.lastname: Morazzoni
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005961:Glucosinolates / Q000378:metabolism / Q000494:pharmacology*; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007096:Imidoesters / Q000494:pharmacology; D017879:Isothiocyanates / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010091:Oximes; D013454:Sulfoxides
chemical_list: D005961:Glucosinolates; D007096:Imidoesters; D017879:Isothiocyanates; D016328:NF-kappa B; D010091:Oximes; D013454:Sulfoxides; C037152:isothiocyanic acid; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C119494:glucoraphanin