Laboratory of B Cell Neoplasia and Lymphoma Unit, Division of Molecular Oncology and Department of Onco-Hematology, Università Vita-Salute and Istituto Scientifico San Raffaele, Milano, Italy.
Immunol Lett. 2013 Sep-Oct;155(1-2):36-9. doi: 10.1016/j.imlet.2013.09.015. Epub 2013 Oct 1.
The BCL2 family members play a central role in regulating programmed cell death (apoptosis) and arbitrating the cellular fate through an accurate balance between pro-apoptotic (BAX, BAK, and BH3-only proteins) and pro-survival (BCL2 and its closest homologues, BCLXL, BCLW and MCL-1) factors. Deregulation of BCL2 family proteins contributes to programmed cell death evasion, that is a hallmark of human cancers and it is often related to (chemo)therapy resistance. High BCL2 levels have been detected in most human lymphoid malignancies, not limited to follicular lymphoma (where the role of BCL2 overexpression is driven by the t[14;18] translocation) but also B-cell chronic lymphocytic leukemia (CLL) and multiple myeloma. For all these reasons, the opportunity to induce apoptosis by targeting BCL2 proteins is considered a potentially promising therapeutic approach in hematological malignancies. BCL2 family inhibition strategies currently explored in phase 1, 2 and 3 clinical trials are essentially two: (1) the use of antisense-based strategies to knockdown BCL2 or BCLXL expression (e.g. oblimersen) or (2) the use of synthetic BH3 mimetics i.e. small molecules binding to anti-apoptotic inhibitors thereby allowing the pro-apoptotic activity of BH3-only molecules (e.g. obatoclax, AT-101, ABT-737 and its derivatives ABT-263 and ABT-199). Several of these drugs demonstrated relevant clinical activity as single-agent or in combination therapy, with the most significant drawbacks in clinical use being represented by challenging pharmacokinetic profile (e.g. iv administration, high-levels of plasma proteins binding) and on-target side effects (e.g. gastrointestinal toxicity and thrombocytopenia). Further clinical development of the current compounds (e.g. ABT-199), showing high efficacy but devoid of the most threatening drug-related toxicities, is eagerly awaited. Hopefully, in the next future, BCL2 inhibitors (alone or in combination with immuno- and/or chemo-therapeutic agents) will represent target-specific drugs expanding our therapeutic armamentarium in the fight against hematologic malignancies.
BCL2 家族成员在调节程序性细胞死亡（细胞凋亡）中发挥核心作用，并通过促凋亡（BAX、BAK 和 BH3 仅蛋白）和抗凋亡（BCL2 和其最接近的同源物，BCLXL、BCL-W 和 MCL-1）因子之间的精确平衡来决定细胞命运。BCL2 家族蛋白的失调导致程序性细胞死亡逃避，这是人类癌症的一个标志，通常与（化疗）耐药有关。在大多数人类淋巴恶性肿瘤中都检测到高 BCL2 水平，不仅限于滤泡性淋巴瘤（BCL2 过表达的作用是由 t[14;18]易位驱动的），还包括 B 细胞慢性淋巴细胞白血病（CLL）和多发性骨髓瘤。由于所有这些原因，通过靶向 BCL2 蛋白诱导细胞凋亡被认为是血液恶性肿瘤中一种有潜在前景的治疗方法。目前在 1、2 和 3 期临床试验中探索的 BCL2 家族抑制策略主要有两种：（1）使用基于反义的策略来敲低 BCL2 或 BCLXL 的表达（例如，oblimersen）；（2）使用合成的 BH3 模拟物，即与抗凋亡抑制剂结合的小分子，从而允许 BH3 仅蛋白（例如，obatoclax、AT-101、ABT-737 及其衍生物 ABT-263 和 ABT-199）的促凋亡活性。这些药物中的几种作为单一药物或联合治疗显示出相关的临床活性，在临床应用中最显著的缺点是具有挑战性的药代动力学特征（例如，iv 给药、高水平的血浆蛋白结合）和靶标相关的副作用（例如，胃肠道毒性和血小板减少症）。目前化合物（例如 ABT-199）的进一步临床开发，显示出高疗效但没有最具威胁性的药物相关毒性，备受期待。希望在未来，BCL2 抑制剂（单独或与免疫和/或化疗药物联合使用）将成为靶向药物，扩大我们在对抗血液恶性肿瘤方面的治疗手段。
