Perimenis Philippos, Galaris Apostolos, Voulgari Alexandra, Prassa Margarita, Pintzas Alexander
Laboratory of Signal Mediated Gene Expression, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
BMC Cancer. 2016 Aug 12;16:624. doi: 10.1186/s12885-016-2606-5.
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.
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.
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.
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.
凋亡抑制蛋白（IAPs）的高表达水平与癌症预后不良相关，并通过干扰半胱天冬酶激活来阻断细胞死亡途径。SMAC模拟物是IAPs的小分子抑制剂，可模拟内源性SMAC并通过中和IAPs促进细胞死亡诱导。
在本研究中，评估了新型SMAC模拟物比瑞那潘和AT-406对结肠直肠腺癌细胞的抗肿瘤活性，并进一步探索IAP与致癌性BRAF或BCL-2或与肿瘤坏死因子相关凋亡诱导配体（TRAIL）的相互作用，以制定合理的联合方案。
研究表明，先用SMAC模拟物预处理，然后与BRAF抑制剂联合治疗，可降低细胞活力、迁移能力，并能非常有效地使结肠直肠肿瘤细胞对凋亡敏感。此外，如中位效应分析所示，TRAIL与SMAC模拟物联合治疗可有效协同使耐药肿瘤细胞对凋亡敏感。最后，比瑞那潘和AT-406可与BCL-2抑制剂ABT-199协同作用，降低高表达BCL-2的腺癌细胞的活力。
在二维和三维培养中提出的IAP拮抗剂比瑞那潘和AT-406的协同合理抗癌联合方案，随后可在体内进一步探索，从精准肿瘤生物学发展到精准医学肿瘤学。
