Dennison Sarah R, Harris Frederick, Phoenix David A
School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK.
School of Forensic and Investigative Science, University of Central Lancashire, Preston PR1 2HE, UK.
Biochimie. 2017 Jun;137:29-34. doi: 10.1016/j.biochi.2017.02.013. Epub 2017 Feb 27.
Here we report the first major example of anionic amphibian host defence peptides (HDPs) with anticancer activity. Maximin H5 (MH5N) is a C-terminally amidated, anionic host defence peptide from toads of the Bombina genus, which was shown to possess activity against the glioma cell line, T98G (EC = 125 μM). The peptide adopted high levels of α-helical structure (57.3%) in the presence of model cancer membranes (DMPC:DMPS in a molar ratio of 10:1). MH5N also showed a strong ability to penetrate these model membranes (Π = 10.5 mN m), which correlated with levels of DMPS (R > 0.98). Taken with the high ability of the peptide to lyse these membranes (65.7%), it is proposed that maximin H5 kills cancer cells via membranolytic mechanisms that are promoted by anionic lipid. It was also found that C-terminally deaminated maximin H5 (MH5C) exhibited lower levels of α-helical structure in the presence of cancer membrane mimics (44.8%) along with a reduced ability to penetrate these membranes (Π = 8.1 mN m) and induce their lysis (56.6%). These data suggested that the two terminal amide groups of native maximin H5 are required for its optimal membranolytic and anticancer activity.
在此，我们报道了具有抗癌活性的阴离子型两栖类宿主防御肽（HDPs）的首个主要实例。大蟾蜍抗菌肽H5（MH5N）是一种来自铃蟾属蟾蜍的C端酰胺化阴离子宿主防御肽，已证明其对胶质瘤细胞系T98G具有活性（EC = 125 μM）。在存在模型癌膜（摩尔比为10:1的二肉豆蔻酰磷脂酰胆碱：二肉豆蔻酰磷脂酰丝氨酸）的情况下，该肽呈现出高水平的α-螺旋结构（57.3%）。MH5N还表现出强大的穿透这些模型膜的能力（Π = 10.5 mN m），这与二肉豆蔻酰磷脂酰丝氨酸的水平相关（R > 0.98）。鉴于该肽具有较高的裂解这些膜的能力（65.7%），推测大蟾蜍抗菌肽H5通过由阴离子脂质促进的膜溶解机制杀死癌细胞。还发现C端脱氨基的大蟾蜍抗菌肽H5（MH5C）在存在癌膜模拟物的情况下呈现出较低水平的α-螺旋结构（44.8%），同时穿透这些膜的能力降低（Π = 8.1 mN m）并诱导其裂解的能力降低（56.6%）。这些数据表明，天然大蟾蜍抗菌肽H5的两个末端酰胺基团是其最佳膜溶解和抗癌活性所必需的。
