Sang Ming, Zhang Jiaxin, Zhuge Qiang
Co-Innovation Center for Sustainable Forestry in Southern China, Key Laboratory of Forest Genetics & Biotechnology, Ministry of Education, Nanjing Forestry University, Nanjing 210037, China.
Co-Innovation Center for Sustainable Forestry in Southern China, Key Laboratory of Forest Genetics & Biotechnology, Ministry of Education, Nanjing Forestry University, Nanjing 210037, China.
Eur J Pharmacol. 2017 May 15;803:138-147. doi: 10.1016/j.ejphar.2017.03.054. Epub 2017 Mar 27.
Some cationic antibacterial peptides, with typical amphiphilic α-helical conformations in a membrane-mimicking environment, exhibit anticancer properties as a result of a similar mechanism of action towards both bacteria and cancer cells. We previously reported the cDNA sequence of the antimicrobial peptide ABP-dHC-Cecropin A precursor cloned from drury (Hyphantria cunea) (dHC). In the present study, we synthesized and structurally characterized ABP-dHC-Cecropin A and its analog, ABP-dHC-Cecropin A-K(24). Circular dichroism spectroscopy showed that ABP-dHC-Cecropin A and its analog adopt a well-defined α-helical structure in a 50% trifluorethanol solution. The cytotoxicity and cell selectivity of these peptides were further examined in three leukemia cell lines and two non-cancerous cell lines. The MTT assay indicated both of these peptides have a concentration-dependent cytotoxic effect in leukemia cells, although the observed cytotoxicity was greater with ABP-dHC-Cecropin A-K(24) treatment, whereas they were not cytotoxic towards the non-cancerous cell lines. Moreover, ABP-dHC-Cecropin A and its analog had a lower hemolytic effect in human red blood cells. Together, these results suggest the peptides are selectively cytotoxic towards leukemia cells. Confocal laser scanning microscopy determined that the peptides were concentrated at the surface of the leukemia cells, and changes in the cell membrane were determined with a permeability assay, which suggested that the anticancer activity of ABP-dHC-Cecropin A and its analog is a result of its presence at the leukemia cell membrane. ABP-dHC-Cecropin A and its analog may represent a novel anticancer agent for leukemia therapy, considering its cancer cell selectivity and relatively low cytotoxicity in normal cells.
一些阳离子抗菌肽在模拟膜的环境中具有典型的两亲性α-螺旋构象，由于对细菌和癌细胞的作用机制相似，因而具有抗癌特性。我们之前报道了从舞毒蛾（Hyphantria cunea）（dHC）中克隆的抗菌肽ABP-dHC-天蚕素A前体的cDNA序列。在本研究中，我们合成了ABP-dHC-天蚕素A及其类似物ABP-dHC-天蚕素A-K(24)，并对其结构进行了表征。圆二色光谱表明，ABP-dHC-天蚕素A及其类似物在50%三氟乙醇溶液中呈现出明确的α-螺旋结构。我们在三种白血病细胞系和两种非癌细胞系中进一步检测了这些肽的细胞毒性和细胞选择性。MTT分析表明，这两种肽在白血病细胞中均具有浓度依赖性细胞毒性作用，尽管ABP-dHC-天蚕素A-K(24)处理时观察到的细胞毒性更大，而它们对非癌细胞系没有细胞毒性。此外，ABP-dHC-天蚕素A及其类似物对人红细胞的溶血作用较低。这些结果共同表明，这些肽对白血病细胞具有选择性细胞毒性。共聚焦激光扫描显微镜确定这些肽集中在白血病细胞表面，通过通透性测定确定了细胞膜的变化，这表明ABP-dHC-天蚕素A及其类似物的抗癌活性是其存在于白血病细胞膜上的结果。考虑到ABP-dHC-天蚕素A及其类似物对癌细胞的选择性以及在正常细胞中相对较低的细胞毒性，它们可能代表一种用于白血病治疗的新型抗癌药物。
