IAP antagonists Birinapant and AT-406 efficiently synergise with either TRAIL, BRAF, or BCL-2 inhibitors to sensitise BRAFV600E colorectal tumour cells to apoptosis
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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DOI：
10.1186/s12885-016-2606-5
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发表时间：
2016-08-12
期刊：
影响因子：
3.8
通讯作者：
Pintzas, Alexander
中科院分区：
文献类型：
--
作者：
Perimenis, Philippos;Galaris, Apostolos;Pintzas, Alexander
背景：凋亡蛋白抑制剂 (IAP) 的高表达水平与癌症预后不良相关，并通过干扰 caspase 激活来阻断细胞死亡途径。 SMAC 模拟物是 IAP 的小分子抑制剂，可模拟内源性 SMAC，并通过中和 IAP 促进诱导细胞死亡。 方法：在这项研究中，评估了新型 SMAC 模拟物 Birinapant 和 AT-406 对结直肠腺癌细胞的抗肿瘤活性，并进一步利用 IAP 与致癌 BRAF 或 BCL-2 或与 TRAIL 的串扰，以实现合理的组合。结果：结果显示，SMAC 模拟物预处理后与 BRAF 抑制剂联合治疗可以降低细胞活力和迁移，并且可以非常有效地使结直肠肿瘤细胞对细胞凋亡敏感。此外，如中值效应分析所示，TRAIL与SMAC模拟物共同治疗可以有效地协同地使耐药肿瘤细胞对细胞凋亡敏感。最后，Birinapant 和 AT-406 可以与 BCL-2 抑制剂 ABT-199 协同作用，降低 BCL-2 高表达腺癌细胞的活力。结论：所提出的 IAP 拮抗剂 Birinapant 和 AT-406 在 2D 和 3D 培养物中的协同合理抗癌联合方案可以在体内进一步开发，从精准肿瘤生物学到精准医学肿瘤学。
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.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.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.