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非肽拟似物 IAP 拮抗剂 ASTX660 增敏结直肠癌细胞发生外在细胞凋亡。

The non-peptidomimetic IAP antagonist ASTX660 sensitizes colorectal cancer cells for extrinsic apoptosis.

机构信息

Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Germany.

出版信息

FEBS Open Bio. 2021 Mar;11(3):714-723. doi: 10.1002/2211-5463.13096. Epub 2021 Feb 19.

DOI:10.1002/2211-5463.13096
PMID:33484626
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7931242/
Abstract

Apoptosis resistance worsens treatment response in cancer and is associated with poor prognosis. Inhibition of anti-apoptotic proteins can restore cell death and improve treatment efficacy. cIAP1, cIAP2, and XIAP belong to the inhibitor of apoptosis protein (IAP) family and block apoptosis. Targeting IAPs with peptides or peptidomimetics mimicking the IAP-antagonizing activity of the cell's endogenous IAP antagonist SMAC (SMAC mimetics) showed promising results and fueled development of novel compounds. ASTX660 belongs to the recently introduced class of non-peptidomimetic IAP antagonists and successfully completed phase I clinical trials. However, ASTX660 has thus far only been evaluated in few cancer entities. Here, we demonstrate that ASTX660 has cell death-promoting activity in colorectal cancer and provide a head-to-head comparison with birinapant, the clinically most advanced peptidomimetic IAP antagonist. ASTX660 facilitates activation of the extrinsic apoptosis pathway upon stimulation with the death ligands TNF and TRAIL and boosts effector caspase activation and subsequent apoptosis. Mechanistically, ASTX660 enhances amplification of death receptor-generated apoptotic signals in a mitochondria-dependent manner. Failure to activate the mitochondria-associated (intrinsic) apoptosis pathway attenuated the apoptosis-promoting effect of ASTX660. Further clinical studies are warranted to highlight the therapeutic potential of ASTX660 in colorectal cancer.

摘要

细胞凋亡抵抗会使癌症患者的治疗反应恶化，并与预后不良相关。抑制抗凋亡蛋白可以恢复细胞死亡并提高治疗效果。cIAP1、cIAP2 和 XIAP 属于凋亡抑制蛋白 (IAP) 家族，可阻断细胞凋亡。用肽或模拟细胞内源性 IAP 拮抗剂 SMAC（SMAC 模拟物）的 IAP 拮抗活性的肽类似物靶向 IAP 显示出有前景的结果，并推动了新型化合物的开发。ASTX660 属于最近引入的非肽类 IAP 拮抗剂类别，已成功完成 I 期临床试验。然而，ASTX660 迄今为止仅在少数几种癌症实体中进行了评估。在这里，我们证明 ASTX660 在结直肠癌中具有促进细胞死亡的活性，并与临床最先进的肽类 IAP 拮抗剂 birinapant 进行了直接比较。ASTX660 可促进 TNF 和 TRAIL 等死亡配体刺激下的外在凋亡途径的激活，并增强效应半胱氨酸蛋白酶的激活和随后的细胞凋亡。在机制上，ASTX660 以依赖线粒体的方式增强了由死亡受体产生的凋亡信号的放大。线粒体相关（内在）凋亡途径的激活失败削弱了 ASTX660 的促凋亡作用。需要进一步的临床研究来强调 ASTX660 在结直肠癌中的治疗潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fa8/7931242/1d034cb76d96/FEB4-11-714-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fa8/7931242/3fb18d5c7d23/FEB4-11-714-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fa8/7931242/08c03221fa58/FEB4-11-714-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fa8/7931242/a88a8317ae70/FEB4-11-714-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fa8/7931242/1d034cb76d96/FEB4-11-714-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fa8/7931242/3fb18d5c7d23/FEB4-11-714-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fa8/7931242/08c03221fa58/FEB4-11-714-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fa8/7931242/a88a8317ae70/FEB4-11-714-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fa8/7931242/a1b12af80066/FEB4-11-714-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4fa8/7931242/1d034cb76d96/FEB4-11-714-g005.jpg

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