| Reference | 1. BMC Cancer. 2016 Aug 12;16:624. doi: 10.1186/s12885-016-2606-5.
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IAP antagonists Birinapant and AT-406 efficiently synergise with either TRAIL,
BRAF, or BCL-2 inhibitors to sensitise BRAFV600E colorectal tumour cells to
apoptosis.
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Perimenis P(1), Galaris A(1), Voulgari A(1), Prassa M(1), Pintzas A(2).
<br>
Author information: <br>
(1)Laboratory of Signal Mediated Gene Expression, Institute of Biology, Medicinal
Chemistry and Biotechnology, National Hellenic Research Foundation, Athens,
Greece.
(2)Laboratory of Signal Mediated Gene Expression, Institute of Biology, Medicinal
Chemistry and Biotechnology, National Hellenic Research Foundation, Athens,
Greece. [email protected].
<br>
BACKGROUND: High expression levels of Inhibitors of Apoptosis Proteins (IAPs)
have been correlated with poor cancer prognosis and block the cell death pathway
by interfering with caspase activation. SMAC-mimetics are small-molecule
inhibitors of IAPs that mimic the endogenous SMAC and promote the induction of
cell death by neutralizing IAPs.<br>
METHODS: In this study, anti-tumour activity of new SMAC-mimetics Birinapant and
AT-406 is evaluated against colorectal adenocarcinoma cells and IAP cross-talk
with either oncogenic BRAF or BCL-2, or with the TRAIL are further exploited
towards rational combined protocols.<br>
RESULTS: It is shown that pre-treatment of SMAC-mimetics followed by their
combined treatment with BRAF inhibitors can decrease cell viability, migration
and can very efficiently sensitize colorectal tumour cells to apoptosis.
Moreover, co-treatment of TRAIL with SMAC-mimetics can efficiently sensitize
resistant tumour cells to apoptosis synergistically, as shown by median effect
analysis. Finally, Birinapant and AT-406 can synergise with BCL-2 inhibitor
ABT-199 to reduce viability of adenocarcinoma cells with high BCL-2 expression.
CONCLUSIONS: Proposed synergistic rational anticancer combined protocols of IAP
antagonists Birinapant and AT-406 in 2D and 3D cultures can be later further
exploited in vivo, from precision tumour biology to precision medical oncology.
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2. Mol Cancer Ther. 2014 Apr;13(4):867-79. doi: 10.1158/1535-7163.MCT-13-0798. Epub
2014 Feb 21.
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Birinapant (TL32711), a bivalent SMAC mimetic, targets TRAF2-associated cIAPs,
abrogates TNF-induced NF-κB activation, and is active in patient-derived
xenograft models.
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Benetatos CA(1), Mitsuuchi Y, Burns JM, Neiman EM, Condon SM, Yu G, Seipel ME,
Kapoor GS, Laporte MG, Rippin SR, Deng Y, Hendi MS, Tirunahari PK, Lee YH,
Haimowitz T, Alexander MD, Graham MA, Weng D, Shi Y, McKinlay MA, Chunduru SK.
<br>
Author information: <br>
(1)Authors/’ Affiliations: TetraLogic Pharmaceuticals, 343 Phoenixville Pike,
Malvern, Pennsylvania; and Tsinghua University School of Medicine, Beijing,
China.
<br>
Erratum in<br>
Mol Cancer Ther. 2014 Sep;13(9):2246-7. Dosage error in article text.
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The acquisition of apoptosis resistance is a fundamental event in cancer
development. Among the mechanisms used by cancer cells to evade apoptosis is the
dysregulation of inhibitor of apoptosis (IAP) proteins. The activity of the IAPs
is regulated by endogenous IAP antagonists such as SMAC (also termed DIABLO).
Antagonism of IAP proteins by SMAC occurs via binding of the N-terminal
tetrapeptide (AVPI) of SMAC to selected BIR domains of the IAPs. Small molecule
compounds that mimic the AVPI motif of SMAC have been designed to overcome
IAP-mediated apoptosis resistance of cancer cells. Here, we report the
preclinical characterization of birinapant (TL32711), a bivalent SMAC-mimetic
compound currently in clinical trials for the treatment of cancer. Birinapant
bound to the BIR3 domains of cIAP1, cIAP2, XIAP, and the BIR domain of ML-IAP in
vitro and induced the autoubiquitylation and proteasomal degradation of cIAP1 and
cIAP2 in intact cells, which resulted in formation of a RIPK1:caspase-8 complex,
caspase-8 activation, and induction of tumor cell death. Birinapant
preferentially targeted the TRAF2-associated cIAP1 and cIAP2 with subsequent
inhibition of TNF-induced NF-κB activation. The activity of a variety of
chemotherapeutic cancer drugs was potentiated by birinapant both in a
TNF-dependent or TNF-independent manner. Tumor growth in multiple primary
patient-derived xenotransplant models was inhibited by birinapant at
well-tolerated doses. These results support the therapeutic combination of
birinapant with multiple chemotherapies, in particular, those therapies that can
induce TNF secretion.
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3. J Natl Cancer Inst. 2014 Feb;106(2):djt440. doi: 10.1093/jnci/djt440.
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Synergistic targeting of AML stem/progenitor cells with IAP antagonist birinapant
and demethylating agents.
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Carter BZ(1), Mak PY, Mak DH, Shi Y, Qiu Y, Bogenberger JM, Mu H, Tibes R, Yao H,
Coombes KR, Jacamo RO, McQueen T, Kornblau SM, Andreeff M.
<br>
Author information: <br>
(1)Affiliations of authors: Section of Molecular Hematology and Therapy,
Department of Leukemia (BZC, PYM, DHM, YS, YQ, HM, ROJ, TM, SMK, MA) and
Department of Bioinformatics and Computational Biology (HY, KRC), University of
Texas M.D. Anderson Cancer Center, Houston, TX; Division of Hematology and
Oncology, Mayo Clinic, Scottsdale, AZ (JMB, RT).
<br>
BACKGROUND: Acute myeloid leukemia (AML) therapy has limited long-term efficacy
because patients frequently develop disease relapse because of the inability of
standard chemotherapeutic agents to target AML stem/progenitor cells. Here, we
identify deregulated apoptotic components in AML stem/progenitor cells and
investigate the individual and combinatorial effects of the novel inhibitor of
apoptosis (IAP) protein antagonist and second mitochondrial-derived activator of
caspases (SMAC) mimetic birinapant and demethylating epigenetic modulators.
METHODS: Protein expression was measured by reversed-phase protein array in AML
patient (n = 511) and normal (n = 21) samples and by western blot in drug-treated
cells. The antileukemic activity of birinapant and demethylating agents was
assessed in vitro and in an in vivo AML mouse xenograft model (n = 10 mice per
group). All statistical tests were two-sided.<br>
RESULTS: Compared with bulk AML cells, CD34(+)38(-) AML stem/progenitors
expressed increased cIAP1 and caspase-8 levels and decreased SMAC levels (one-way
analysis of variance followed by Tukey/’s multiple comparison test, P < .001).
Birinapant induced death receptor-/caspase-8-mediated apoptosis in AML cells,
including in AML stem/progenitor cells, but not in normal CD34(+) cells.
Demethylating agents modulated extrinsic apoptosis pathway components and, when
combined with birinapant, were highly synergistic in vitro (combination index <
1), and also more effective in vivo (P < .001, by Student t test, for the median
survival of birinapant plus 5-azacytadine vs birinapant alone or vs controls).
CONCLUSIONS: cIAP1, SMAC, and caspase-8 appear to play a role in AML stem cell
survival, and synergistic targeting of these cells with birinapant and
demethylating agents shows potential utility in leukemia therapy.
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