Bombesin analogue-mediated delivery preferentially enhances the cytotoxicity of a mitochondria-disrupting peptide in tumor cells.
Bombesin analogue-mediated delivery preferentially enhances the cytotoxicity of a mitochondria-disrupting peptide in tumor cells.
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DOI：
10.1371/journal.pone.0057358
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lu X
中科院分区：
文献类型：
--
作者：
Yang H;Cai H;Wan L;Liu S;Li S;Cheng J;Lu X
肿瘤归巢肽可识别肿瘤细胞上的特定标记物，已显示出作为靶向癌症治疗药物载体的潜力。Bombesin受体在广泛的人类肿瘤中经常过度表达或异位表达。Bombesin及其类似物作为药物载体被广泛应用于肿瘤成像和肿瘤治疗。然而，在以前的研究中使用的药物，包括放射性和化疗药物，通常是小分子的。线粒体干扰肽在进入肿瘤细胞后使线粒体去极化并引发细胞凋亡。我们感兴趣的是，bombesin类似物Bn（6-14）是否含有bombesin受体结合基元，可以特异性地将线粒体破坏肽B28传递到肿瘤细胞。为此，我们通过在n端将B28与Bn（6-14）偶联，构建了一个嵌合肽B28Bn（6-14）。B28Bn（6-14）对肿瘤细胞的毒性比未偶联的B28强得多。B28Bn（6 ~ 14）在肿瘤细胞（1.7 ~ 3.5µM）中的IC50值比B28低约10倍。然而，B28与缺乏bombesin受体结合基序的Bn（2-7）结合并没有增加其细胞毒性。B28Bn（6-14）在肿瘤细胞（1.7 ~ 3.5µM）中的IC50值比正常细胞（10.8 ~ 16.8µM）低3 ~ 10倍。我们发现B28Bn（6-14）与肿瘤细胞的选择性结合依赖于Bn（6-14）。B28Bn（6-14）进入肿瘤细胞后，在线粒体中积累，引发caspase依赖性细胞凋亡。瘤内和腹腔注射B28Bn（6-14）可显著抑制小鼠DU145肿瘤异种移植物的生长。这些结果表明，B28Bn（6-14）能够将线粒体干扰肽传递到肿瘤细胞中，B28Bn（6-14）可以作为一种新的抗癌药物进一步开发。
Tumor-homing peptides that recognize specific markers on tumor cells have shown potential as drug carriers for targeted cancer therapy. Bombesin receptors are frequently overexpressed or ectopically expressed in a wide range of human tumors. Bombesin and its analogues have been widely used as drug carriers for tumor imaging and tumor therapy. However, the cargos used in previous studies, including radioactive and chemotherapeutic agents, are usually small molecules. Mitochondrial-disrupting peptides depolarize the mitochondria and trigger apoptosis after entering tumor cells. We are interested in whether the bombesin analogue, Bn(6–14), which contains a bombesin receptor-binding motif, can specifically deliver the mitochondria-disrupting peptide, B28, to tumor cells. To this end, we created a chimeric peptide, B28Bn(6–14), by conjugating B28 to Bn(6–14) at its N-terminus. The cytotoxicity of B28Bn(6–14) in tumor cells was much stronger than unconjugated B28. The IC50 values of B28Bn(6–14) in tumor cells (1.7–3.5 µM) were approximately 10 times lower than B28. However, conjugation of B28 to Bn(2–7), which lacks the bombesin receptor-binding motif, did not increase its cytotoxicity. In addition, the IC50 values of B28Bn(6–14) in tumor cells (1.7–3.5 µM) was 3–10 times lower than in normal cells (10.8–16.8 µM). We found that selective binding of B28Bn(6–14) to tumor cells is Bn(6–14)-dependent. Upon entering the tumor cell, B28Bn(6–14) accumulated in the mitochondria and triggered caspase-dependent apoptosis. Intratumoral and intraperitoneal administration of B28Bn(6–14) substantially suppressed the growth of DU145 tumor xenografts in mice. These results demonstrate that Bn(6–14) is able to deliver the mitochondria-disrupting peptide to tumor cells, and B28Bn(6–14) should be further developed as novel anti-cancer agent.
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影响因子：
13.8
作者：
Combet, C;Blanchet, C;Deléage, G
通讯作者：
Deléage, G
影响因子：
4.8
作者：
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作者：
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