De Gejing, Ko Jae-Kyun, Tan Tao, Zhu Hua, Li Haichang, Ma Jianjie
Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
Department of Physiology and Biophysics, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ, USA. Mutagenex Inc., 1 Jill Court, Hillsborough, NJ, USA.
Oncotarget. 2014 Sep 15;5(17):7734-47. doi: 10.18632/oncotarget.2301.
Amphipathic tail-anchoring peptide (ATAP) derived from the human anti-apoptotic protein Bfl-1 is a potent inducer of apoptosis by targeting mitochondria permeability transition. By linking ATAP to an internalizing RGD peptide (iRGD), selective targeting for ATAP to tumor cell was achieved. Confocal fluorescence microscopy showed that ATAP-iRGD could penetrate into cancer cells and distribute along the mitochondria network. ATAP-iRGD triggered mitochondria-dependent cell death through release of cytochrome c. In an effort to promote ATAP-iRGD physiochemical properties to approach clinic application, amino acid substitution and chemical modification were made with ATAP-iRGD to improve its bioactivity. One of these modified peptides, ATAP-iRGD-M8, was with improved stability and aqueous solubility without compromising in vitro cytotoxicity in cultured cancer cells. In vivo xenograft studies with multiple prostate cancer cell lines showed that intravenous administration of ATAP-iRGD-M8 suppressed tumor growth. Toxicological studies revealed that repetitive intravenous administration of ATAP-iRGD-M8 did not produce significant toxicity in the SV129 mice. Our data suggest that ATAP-iRGD-M8 is a promising agent with high selectivity and limited systemic toxicity for prostate cancer treatment.
源自人类抗凋亡蛋白Bfl-1的两亲性尾部锚定肽（ATAP）通过靶向线粒体通透性转变，是一种有效的细胞凋亡诱导剂。通过将ATAP与内化RGD肽（iRGD）连接，实现了ATAP对肿瘤细胞的选择性靶向。共聚焦荧光显微镜显示，ATAP-iRGD可穿透癌细胞并沿线粒体网络分布。ATAP-iRGD通过细胞色素c的释放引发线粒体依赖性细胞死亡。为了促进ATAP-iRGD的理化性质以接近临床应用，对ATAP-iRGD进行了氨基酸取代和化学修饰以提高其生物活性。其中一种修饰肽ATAP-iRGD-M8具有更高的稳定性和水溶性，同时不影响对培养癌细胞的体外细胞毒性。对多种前列腺癌细胞系进行的体内异种移植研究表明，静脉注射ATAP-iRGD-M8可抑制肿瘤生长。毒理学研究表明，重复静脉注射ATAP-iRGD-M8在SV129小鼠中不会产生明显毒性。我们的数据表明，ATAP-iRGD-M8是一种有前景的药物，对前列腺癌治疗具有高选择性和有限的全身毒性。
