Suppression of human prostate tumor growth in mice by a cytolytic D-, L-amino acid peptide: Membrane lysis, increased necrosis, and inhibition of prostate-specific antigen secretion
Suppression of human prostate tumor growth in mice by a cytolytic D-, L-amino acid peptide: Membrane lysis, increased necrosis, and inhibition of prostate-specific antigen secretion
复制标题
DOI：
10.1158/0008-5472.can-04-1438
复制
发表时间：
2004-08-15
期刊：
影响因子：
11.2
通讯作者：
Shai, Y
中科院分区：
文献类型：
--
作者：
Papo, N;Braunstein, A;Shai, Y
基因编码的宿主防御肽被用作天然免疫的一部分，其中许多通过直接裂解病原体的细胞膜来发挥作用。这些多肽中有几个显示了抗癌活性吗？在体外，但由于血清灭活，不能在体内使用。我们设计了一种由D-氨基酸和L-氨基酸(非对映异构体)组成的15个氨基酸的多肽，它针对雄激素非依赖性和雄激素依赖性的人前列腺癌细胞株(CL1、22Rv1和LN-CAP)。最重要的是，我们观察到CL1和22Rv1异种移植瘤的生长完全停止；肿瘤内使用非甾体治疗。这也伴随着22Rv1异种移植所分泌的前列腺特异性抗原血清水平的降低。此外，非对映异构体与常规化疗药物有协同作用。而亲本全L氨基酸仅在体外具有较高的活性，不能区分肿瘤细胞和非肿瘤细胞。荧光共聚焦显微镜、组织病理学检查和细胞通透性研究(跨膜电位的去极化和包裹的染料的释放)表明，当多肽达到阈值浓度后，就会发生死亡的坏死机制。它的破坏性杀伤作用和非对映异构体的简单序列使其成为一种有吸引力的候选化疗药物，具有新的作用模式，有可能被进一步开发用于前列腺癌的治疗。
Gene-encoded host defense peptides are used as part of the innate immunity, and many of them act by directly lysing the cell membrane of the pathogen. A few of these peptides showed anticancer activity it? vitro but could not be used in vivo because of their inactivation by serum. We designed a 15-amino acid peptide, composed of D- and L-amino acids (diastereomer), which targets both androgen-independent and androgen-dependent human prostate carcinoma cell lines (CL1, 22RV1, and LN-CaP). Most importantly, we observed a complete arrest of growth in CL1 and 22RV1 xenografts; treated intratumorally with the diastercomer. This was also accompanied by a lowering of prostate-specific antigen serum levels secreted by the 22RV1 xenograft. Furthermore, the diastereomer synergized with conventional chemotherapeutics. In contrast, the parental all L-amino acids peptide was highly active only in vitro and could not discriminate between tumor and nontumor cells. Fluorescent confocal microscopy, histopathologic examination, and cell permeability studies (depolarization of transmembrane potential and release of an encapsulated dye) suggest a necrotic mechanism of killing, after a threshold concentration of peptide has been reached. Its destructive killing effect and the simple sequence of the diastereomer make it an attractive chemotherapeutic candidate possessing a new mode of action, with potential to be developed additionally for the treatment of prostate carcinoma.