Antitumor Activity of a Novel Homodimeric SMAC Mimetic in Ovarian Carcinoma

• Published in: Molecular pharmaceutics Vol. 11; no. 1; pp. 283 - 293
• Main Authors: Gatti, Laura, De Cesare, Michelandrea, Ciusani, Emilio, Corna, Elisabetta, Arrighetti, Noemi, Cominetti, Denis, Belvisi, Laura, Potenza, Donatella, Moroni, Elisabetta, Vasile, Francesca, Lecis, Daniele, Delia, Domenico, Castiglioni, Vittoria, Scanziani, Eugenio, Seneci, Pierfausto, Zaffaroni, Nadia, Perego, Paola
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 06.01.2014
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis Regulatory Proteins - pharmacology; Biomimetic Materials - pharmacology; Blotting, Western; Carrier Proteins - pharmacology; Cell Proliferation - drug effects; Enzyme-Linked Immunosorbent Assay; Female; Humans; Intracellular Signaling Peptides and Proteins - pharmacology; Magnetic Resonance Spectroscopy; Mice; Mitochondrial Proteins - pharmacology; Molecular Dynamics Simulation; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - pathology; TNF-Related Apoptosis-Inducing Ligand - metabolism; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - metabolism; ovarian carcinoma; SMAC mimetics; apoptosis; TRAIL
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/mp4004578

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.