Dharap Sonia S, Minko Tamara
Department of Pharmaceutics, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, USA.
Pharm Res. 2003 Jun;20(6):889-96. doi: 10.1023/a:1023839319950.
The purpose of this work was to construct and evaluate a novel targeted proapoptotic peptide for cancer treatment.
The peptide consisted of luteinizing hormone-releasing hormone (LHRH) as a targeting moiety specific to LHRH receptors and a synthetic BCL-2 homology 3 (BH3) domain peptide as an apoptosis inducer and a suppressor of antiapoptotic cellular defense. Anticancer activity of the peptide was evaluated on different cancer cell lines.
The targeting receptor to LHRH peptide is overexpressed in several cancer cell lines but is not expressed in healthy human visceral organs. LHRH and BH3 peptides when applied separately did not demonstrate cellular toxicity. In contrast, the LHRH-BH3 peptide was toxic in several cancer cell lines. Coincubation of LHRH and LHRH-BH3 peptides significantly decreased cytotoxicity of the latter. It was found that the LHRH-BH3 peptide induced apoptosis by simultaneous inhibition of the antiapoptotic function of BCL-2 protein family and activation of caspase-dependent signaling pathway.
The proposed anticancer proapoptotic LHRH-BH3 peptide simultaneously affects two molecular targets: 1) extracellular cancer-specific LHRH receptors and 2) the intracellular controlling mechanisms of apoptosis. The results of this work may be used to design novel approaches for the treatment of various cancers.
本研究旨在构建并评估一种用于癌症治疗的新型靶向促凋亡肽。
该肽由作为促黄体生成素释放激素（LHRH）受体特异性靶向部分的促黄体生成素释放激素（LHRH）和作为凋亡诱导剂及抗凋亡细胞防御抑制剂的合成BCL-2同源3（BH3）结构域肽组成。在不同癌细胞系上评估该肽的抗癌活性。
LHRH肽的靶向受体在几种癌细胞系中过表达，但在健康人体内脏器官中不表达。单独应用LHRH和BH3肽时未显示细胞毒性。相反，LHRH-BH3肽在几种癌细胞系中具有毒性。LHRH和LHRH-BH3肽共同孵育显著降低了后者的细胞毒性。发现LHRH-BH3肽通过同时抑制BCL-2蛋白家族的抗凋亡功能和激活半胱天冬酶依赖性信号通路诱导凋亡。
所提出的抗癌促凋亡LHRH-BH3肽同时影响两个分子靶点：1）细胞外癌症特异性LHRH受体和2）细胞内凋亡控制机制。本研究结果可用于设计治疗各种癌症的新方法。
