SMI of Bcl-2 TW-37 is active across a spectrum of B-cell tumors irrespective of their proliferative and differentiation status.
SMI of Bcl-2 TW-37 is active across a spectrum of B-cell tumors irrespective of their proliferative and differentiation status.
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DOI：
10.1186/1756-8722-2-8
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发表时间：
2009-02-16
影响因子：
28.5
通讯作者：
Mohammad RM
中科院分区：
文献类型：
--
作者：
Al-Katib AM;Sun Y;Goustin AS;Azmi AS;Chen B;Aboukameel A;Mohammad RM
Bcl2蛋白家族对恶性B淋巴细胞的生死至关重要。使用小分子抑制剂(SMI)干扰它们的活性是治疗B细胞肿瘤的一种新的治疗策略。我们评估了TW-37对一系列人类B细胞系、新鲜患者样本和动物异种移植模型的疗效，TW-37是一种非肽类的Bcl2 SMI。应用细胞化学和分子生物学方法，如吖啶橙/溴化乙锭比色法、免疫共沉淀法和免疫印迹法、半胱氨酸天冬氨酸氨基转移酶发光活性分析和DNA片段化分析等，研究了TW-37对不同B细胞系、患者来源标本以及动物异种移植模型的作用。纳摩尔浓度的TW-37能够诱导新鲜样本和已建立的细胞系的凋亡，其IC50在大多数情况下为165-320 nM。细胞凋亡与B细胞肿瘤的增殖状态或病理类型无关。TW-37可阻断Bim-Bclxl和Bim-Mcl-1异二聚化，并通过激活caspase-9、-3、PARP和DNA片段化诱导细胞凋亡。TW-37经尾静脉给药(40 mg/kg×3天)对SCID荷瘤小鼠有明显的肿瘤生长抑制(T/C)、肿瘤生长延迟(T-C)和Log10杀伤作用。TW-37未能诱导Bc l-2蛋白水平的改变，提示对基线Bc l-2家族蛋白的评估可用于预测对该药物的反应。这些发现表明TW-37在人类B细胞肿瘤中的活性，并支持将Bcl2系统作为一种治疗策略的概念，而不考虑B细胞分化的阶段。
The Bcl-2 family of proteins is critical to the life and death of malignant B-lymphocytes. Interfering with their activity using small-molecule inhibitors (SMI) is being explored as a new therapeutic strategy for treating B-cell tumors. We evaluated the efficacy of TW-37, a non-peptidic SMI of Bcl-2 against a range spectrum of human B-cell lines, fresh patient samples and animal xenograft models. Multiple cytochemical and molecular approaches such as acridine orange/ethidium bromide assay for apoptosis, co-immunoprecipitation of complexes and western blot analysis, caspase luminescent activity assay and apoptotic DNA fragmentation assay were used to demonstrate the effect of TW-37 on different B-cell lines, patient derived samples, as well as in animal xenograft models. Nanomolar concentrations of TW-37 were able to induce apoptosis in both fresh samples and established cell lines with IC50 in most cases of 165–320 nM. Apoptosis was independent of proliferative status or pathological classification of B-cell tumor. TW-37 was able to block Bim-Bcl-XL and Bim-Mcl-1 heterodimerization and induced apoptosis via activation of caspases -9, -3, PARP and DNA fragmentation. TW-37 administered to tumor-bearing SCID mice led to significant tumor growth inhibition (T/C), tumor growth delay (T-C) and Log10kill, when used at its maximum tolerated dose (40 mg/kg × 3 days) via tail vein. TW-37 failed to induce changes in the Bcl-2 proteins levels suggesting that assessment of baseline Bcl-2 family proteins can be used to predict response to the drug. These findings indicate activity of TW-37 across the spectrum of human B-cell tumors and support the concept of targeting the Bcl-2 system as a therapeutic strategy regardless of the stage of B-cell differentiation.
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