文章：

解码并解锁癌细胞对BCL-2的依赖性

Decoding and unlocking the BCL-2 dependency of cancer cells

原文发布日期：2013-06-20

DOI: 10.1038/nrc3538

类型: Review Article

开放获取: 否

要点：

1. The balance between pro- and anti-apoptotic activities of BCL-2 family members is tipped towards survival in many cancer cells, thus allowing them to survive various stressful environments, tumour stress phenotypes and/or oncogene-induced death signals.
2. As death signals may persist during tumour progression, cancer cells may be addicted to these survival mechanisms and be in a state of dependence on 'BCL-2-like' (BCL-2L) anti-apoptotic proteins.
3. Survival of 'BCL-2L-dependent' cancer cells relies on the maintenance of protein–protein complexes in which the BH3 domain of some pro-apoptotic BCL-2 family members engages a hydrophobic groove at the surface of anti-apoptotic BCL-2L proteins.
4. Structural characterization of the BH3-binding interface of anti-apoptotic BCL-2L proteins has led to the identification of small-molecule BH3 mimetics that disrupt key interactions and promote cancer cell apoptosis by on-target effects.
5. A dual BCL-2 and BCL-X_L inhibitor and a specific BCL-2 inhibitor have shown clinical activity in haematological malignancies. The dual inhibitor induces dose-limiting thrombocytopenia owing to BCL-X_L inhibition.
6. Finely-tuned inhibition of BCL-X_L and of MCL1 in cancer cells by new and selective drugs remains a challenge and a necessity.
7. Understanding the exact effects of inhibitors on endogenous (membrane-localized) complexes, identifying predictive biomarkers for drug efficacy and circumscribing the global biological effects of these compounds is also required.

要点翻译：

1. 在许多癌细胞中，BCL-2家族成员促凋亡与抗凋亡活性的平衡倾向于存活，这使得它们能够在各种应激环境、肿瘤应激表型和/或癌基因诱导的死亡信号中存活下来。
2. 由于死亡信号可能在肿瘤进展期间持续存在，癌细胞可能对这些生存机制产生依赖，处于对"BCL-2样"（BCL-2L）抗凋亡蛋白的依赖状态。
3. "BCL-2L依赖性"癌细胞的存活依赖于蛋白质-蛋白质复合物的维持，其中某些促凋亡BCL-2家族成员的BH3结构域与抗凋亡BCL-2L蛋白表面的疏水沟槽结合。
4. 通过对抗凋亡BCL-2L蛋白BH3结合界面的结构表征，研究人员发现了小分子BH3模拟物，这些模拟物可通过靶向作用破坏关键相互作用并促进癌细胞凋亡。
5. 一种双重BCL-2和BCL-XL抑制剂及一种特异性BCL-2抑制剂已在血液系统恶性肿瘤中显示出临床活性。双重抑制剂因抑制BCL-XL而引发剂量限制性血小板减少症。
6. 通过新型选择性药物对癌细胞中BCL-XL和MCL1进行精细调控的抑制仍然是一个挑战和必要需求。
7. 同时需要理解抑制剂对内源性（膜定位）复合物的确切影响，确定药物疗效的预测性生物标志物，并界定这些化合物的整体生物学效应。

英文摘要：

Cancer cells are subject to many apoptotic stimuli that would kill them were it not for compensatory prosurvival alterations. BCL-2-like (BCL-2L) proteins contribute to such aberrant behaviour by engaging a network of interactions that is potent at promoting survival but that is also fragile: inhibition of a restricted number of interactions may suffice to trigger cancer cell death. Currently available and novel compounds that inhibit these interactions could be efficient therapeutic agents if this phenotype of BCL-2L dependence was better understood at a molecular, cellular and systems level and if it could be diagnosed by relevant biomarkers.

摘要翻译： 

癌细胞受到多种凋亡刺激，若非其通过代偿性促生存改变得以幸存，早应死亡。BCL-2样（BCL-2L）蛋白通过构建一个强效但脆弱的相互作用网络促成这种异常行为：该网络虽高效促进生存，但只需抑制其中少数关键相互作用即可触发癌细胞死亡。若能从分子、细胞及系统层面深入理解这种BCL-2L依赖性表型，并通过相关生物标志物实现诊断，则现有及新型抑制这些相互作用的化合物有望成为高效治疗药物。

原文链接：

Decoding and unlocking the BCL-2 dependency of cancer cells