Abstract
BackgroundHigh 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.MethodsIn 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.ResultsIt 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.ConclusionsProposed 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2606-5) contains supplementary material, which is available to authorized users.
Highlights
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
We investigate the effect of IAPs inhibition by recently developed second mitochondria-derived activator of caspases (SMAC)-mimetics Birinapant and AT-406 in colorectal tumour cells, their cross-talk with the TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptotic pathway, BRAF and B-cell lymphoma 2 (BCL-2) oncogenic pathways and the underlying mechanisms that can efficiently overcome tumour resistance to apoptosis
Efficient protocols of inhibition of IAPs activity and anti-apoptotic effect are presented by using Birinapant or AT-406 alone and in their combinations with either TRAIL or with other inhibitors of prosurvival pathways, like BRAF-MEK and BCL-2
Summary
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. Colorectal cancer (CRC) is one of the most common malignancies worldwide. In CRC, like in other tumour types, rational combination treatments can overcome resistance. A variety of anti-tumour therapeutics, especially small-molecule inhibitors against IAPs (IAP antagonist compounds (IAC), SMAC-mimetics) are being designed and clinically tested [7, 8]. Since targeting of IAPs can be only partially efficient as anti-cancer therapy, rational combination treatments with other targeted molecules against driver oncogenes, or apoptotic factors can be crucial to overcome tumour resistance
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