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Antitumor Activity of a Novel Homodimeric SMAC Mimetic in Ovarian Carcinoma
journal contribution
posted on 2014-01-06, 00:00 authored by Laura Gatti, Michelandrea De Cesare, Emilio Ciusani, Elisabetta Corna, Noemi Arrighetti, Denis Cominetti, Laura Belvisi, Donatella Potenza, Elisabetta Moroni, Francesca Vasile, Daniele Lecis, Domenico Delia, Vittoria Castiglioni, Eugenio Scanziani, Pierfausto Seneci, Nadia Zaffaroni, Paola PeregoTreatment 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.
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tumor cell resistancecarcinoma cells subcutaneously xenograftednovel homodimeric SMACmcell sensitivity assaysSM 83 downmodulateddimeric SM 83SM 83Novel Homodimeric SMAC Mimeticterminal phenyl groupsapoptotic cell deathtumor necrosis factornovel SMACm SM 83novel proapoptotic agentstumor volume inhibitionnovel treatment optionsTNFBIR 2 domain
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