Selective Apoptotic Killing of Solid and Hematologic Tumor Cells by Bombesin-Targeted Delivery of Mitochondria-Disrupting Peptides
Selective Apoptotic Killing of Solid and Hematologic Tumor Cells by Bombesin-Targeted Delivery of Mitochondria-Disrupting Peptides
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通过铃蟾肽靶向递送线粒体破坏肽选择性凋亡杀死实体瘤和血液肿瘤细胞
DOI：
10.1021/mp900280s
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发表时间：
2010-03-01
影响因子：
4.9
通讯作者：
Lu, Xiaofeng
中科院分区：
文献类型：
--
作者：
Cai, Huawei;Yang, Hao;Lu, Xiaofeng
肿瘤归巢肽由于其特异性结合并进入肿瘤细胞和肿块的能力而成为肿瘤成像和靶向治疗的有吸引力的工具。蛙皮素及其类似物显示出将放射性和化学治疗剂靶向递送至多种实体肿瘤的前景。在这里，我们描述了蛙皮素靶向递送毒性肽到实体瘤细胞和白血病细胞。我们发现蛙皮素特异性结合实体瘤细胞和白血病细胞，具有相似的亲和力。与蛙皮素偶联显著（5-15倍）增强了三种细胞分裂素破坏肽（KLA、B27和B28）在实体瘤细胞和白血病细胞中的细胞毒性，通过提高它们的结合亲和力。蛙皮素定向肽（KB、BB 27和BB 28）含有相同的蛙皮素前导序列，但具有不同的caspase破坏肽，其选择性地诱导实体瘤细胞和白血病细胞系中的caspase依赖性凋亡。这些肽（BB 27，3-5 μ mol/L; BB 28，4-6 μ mol/L）对实体瘤细胞和白血病细胞的1050值比对正常细胞的1050值低约5-10倍。BB 27和BB 28还在来自患有急性髓性白血病的患者（n = 4）的原代白血病细胞中显示出细胞毒性。瘤内注射（10 mg/kg）和腹腔注射（20 mg/kg）BB 27和BB 28对K562移植瘤生长有明显抑制作用，无明显全身毒性。我们的研究结果表明，蛙皮素定向的抗肿瘤肽BB 27和BB 28不仅可用于实体瘤，而且可用于血液肿瘤的治疗。
Tumor-homing peptides are attractive tools for tumor imaging and targeted therapy due to their ability to specifically bind and enter tumor cells and masses. Bombesin and its analogues show promise for the targeted delivery of radioactive and chemotherapeutic agents to a wide variety of solid tumors. Here, we describe the bombesin-targeted delivery of toxic peptides to solid tumor cells and leukemia cells. We found that bombesin specifically bound to solid tumor cells and leukemia cells with similar affinity. Conjugation to bombesin significantly (5-15 times) enhanced the cytotoxicity of three mitochondria-disrupting peptides (KLA, B27, and B28) in solid tumor cells and leukemia cells through improvement of their binding affinity. The bombesin-directed peptides (KB, BB27, and BB28) contained the same bombesin leader sequence but had different mitochondria-disrupting peptides, which selectively induced caspase-dependent apoptosis in solid tumor cells and leukemia cell lines. The 1050 values of these peptides (BB27, 3-5 mu mol/L; BB28, 4-6 mu mol/L) for solid tumor cells and leukemia cells are approximately 5-10 times lower than the 1050 values for normal cells. BB27 and BB28 also displayed cytotoxicity in primary leukemia cells from patients (n = 4) with acute myeloid leukemia. Intratumoral (10 mg/kg) and intraperitoneal (20 mg/kg) injection of BB27 and BB28 exerted substantial inhibition on K562 tumor xenograft growth without obvious systematic toxicity. Our results suggest that the bombesin-directed mitochondria-disrupting peptides BB27 and BB28 might be used as therapeutic agents not only for solid tumors but also for hematologic tumors.