Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
Exp Hematol. 2011 Mar;39(3):282-92. doi: 10.1016/j.exphem.2010.11.010. Epub 2010 Dec 5.
The chemokine receptor CXCR4 and its ligand CXCL12 are involved in the progression and dissemination of a diverse number of solid and hematological malignancies. Binding CXCL12 to CXCR4 activates a variety of intracellular signal transduction pathways that regulate cell chemotaxis, adhesion, survival, proliferation, and apoptosis.
Here, we demonstrate that the CXCR4 antagonist, 4F-benzoyl-TN14003 (BKT140), but not AMD3100, exhibits a CXCR4-dependent preferential cytotoxicity toward malignant cells of hematopoietic origin. BKT140 significantly and preferentially stimulated multiple myeloma apoptotic cell death. BKT140 treatment induced morphological changes, phosphatidylserine externalization, decreased mitochondrial membrane potential, caspase-3 activation, sub-G1 arrest, and DNA double-stranded breaks.
In vivo, subcutaneous injections of BKT140 significantly reduced, in a dose-dependent manner, the growth of human acute myeloid leukemia and multiple myeloma xenografts. Tumors from animals treated with BKT140 were smaller in size and weights, had larger necrotic areas and high apoptotic scores.
Taken together, these results suggest a potential therapeutic use for BKT140 in multiple myeloma and leukemia patients.
趋化因子受体 CXCR4 及其配体 CXCL12 参与多种实体瘤和血液恶性肿瘤的进展和扩散。CXCL12 与 CXCR4 结合可激活多种细胞内信号转导通路，调节细胞趋化性、黏附性、存活、增殖和凋亡。
在这里，我们证明 CXCR4 拮抗剂 4F-苯甲酰-TN14003（BKT140）而非 AMD3100 对造血来源的恶性细胞具有 CXCR4 依赖性的优先细胞毒性。BKT140 可显著且优先地刺激多发性骨髓瘤细胞凋亡。BKT140 处理诱导了形态变化、磷脂酰丝氨酸外翻、线粒体膜电位降低、半胱天冬酶-3 激活、亚 G1 期阻滞和 DNA 双链断裂。
在体内，BKT140 的皮下注射以剂量依赖性方式显著降低了人急性髓系白血病和多发性骨髓瘤异种移植物的生长。用 BKT140 处理的动物的肿瘤体积较小，重量较轻，坏死面积较大，凋亡评分较高。
综上所述，这些结果表明 BKT140 在多发性骨髓瘤和白血病患者中有潜在的治疗用途。
