title: Antitumor activity of a novel homodimeric SMAC mimetic in ovarian carcinoma.
abstract: Treatment of ovarian carcinoma often fails to be curative because of drug resistance, and many efforts are directed to overcome tumor cell resistance by increasing apoptosis induction. The potential of second mitochondria-derived activator of caspases (SMAC) mimetics (SMACm) has appeared in preclinical studies, but novel proapoptotic agents of this class with improved pharmacological profile are needed. To identify novel treatment options for ovarian carcinoma by interfering with antiapoptotic factors, in the present study a novel homodimeric SMACm (SM83) was employed in preclinical models both in vitro and in vivo. An investigation of the structural features of dimeric SM83 as compared to a closely related reference compound indicated slight differences, likely because of the interaction between one of the terminal phenyl groups and triazole rings of SM83 with the BIR2 domain. Although SM83 per se did not inhibit cell proliferation, it displayed a synergistic effect in combination with TNF-related apoptosis inducing ligand (TRAIL) in cell sensitivity assays. Because the tumor microenvironment is a reservoir of cytokines that may act in conjunction with SMACm to affect tumor growth, the activity of the novel compound was tested in vivo in ovarian carcinoma cells subcutaneously xenografted into immunodeficient mice. A significant tumor volume inhibition was observed together with activation of caspase 3 and apoptotic cell death. A biochemical analysis of tumor necrosis factor (TNF) and TRAIL content in specimens from xenografted mice indicated that SM83 downmodulated the levels of human TNF in plasma samples and tended to upmodulate human TRAIL levels in tumors. Thus, TRAIL appears to contribute to the antitumor activity of novel SMACm SM83 in subcutaneously grown ovarian carcinoma. Overall, our results indicate that SM83 is an attractive candidate for further development.
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori , Via Amadeo 42, Milan 20133, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Gatti
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.forename: Emilio
authors.initials: E
authors.lastname: Ciusani
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Corna
authors.forename: Noemi
authors.initials: N
authors.lastname: Arrighetti
authors.forename: Denis
authors.initials: D
authors.lastname: Cominetti
authors.forename: Laura
authors.initials: L
authors.lastname: Belvisi
authors.forename: Donatella
authors.initials: D
authors.lastname: Potenza
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Moroni
authors.forename: Francesca
authors.initials: F
authors.lastname: Vasile
authors.forename: Daniele
authors.initials: D
authors.lastname: Lecis
authors.forename: Domenico
authors.initials: D
authors.lastname: Delia
authors.forename: Vittoria
authors.initials: V
authors.lastname: Castiglioni
authors.forename: Eugenio
authors.initials: E
authors.lastname: Scanziani
authors.forename: Pierfausto
authors.initials: P
authors.lastname: Seneci
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.forename: Paola
authors.initials: P
authors.lastname: Perego
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000494:pharmacology*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D024101:Mitochondrial Proteins / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C412403:DIABLO protein, human; C499605:Diablo protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; C439524:TNF protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha