10.1021/mp4004578.s001
Laura Gatti
Laura
Gatti
Michelandrea De Cesare
Michelandrea De
Cesare
Emilio Ciusani
Emilio
Ciusani
Elisabetta Corna
Elisabetta
Corna
Noemi Arrighetti
Noemi
Arrighetti
Denis Cominetti
Denis
Cominetti
Laura Belvisi
Laura
Belvisi
Donatella Potenza
Donatella
Potenza
Elisabetta Moroni
Elisabetta
Moroni
Francesca Vasile
Francesca
Vasile
Daniele Lecis
Daniele
Lecis
Domenico Delia
Domenico
Delia
Vittoria Castiglioni
Vittoria
Castiglioni
Eugenio Scanziani
Eugenio
Scanziani
Pierfausto Seneci
Pierfausto
Seneci
Nadia Zaffaroni
Nadia
Zaffaroni
Paola Perego
Paola
Perego
Antitumor Activity of a Novel Homodimeric SMAC Mimetic
in Ovarian Carcinoma
American Chemical Society
2014
tumor cell resistance
carcinoma cells subcutaneously xenografted
novel homodimeric SMACm
cell sensitivity assays
SM 83 downmodulated
dimeric SM 83
SM 83
Novel Homodimeric SMAC Mimetic
terminal phenyl groups
apoptotic cell death
tumor necrosis factor
novel SMACm SM 83
novel proapoptotic agents
tumor volume inhibition
novel treatment options
TNF
BIR 2 domain
2014-01-06 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Antitumor_Activity_of_a_Novel_Homodimeric_SMAC_Mimetic_in_Ovarian_Carcinoma/2335960
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.