Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun, 130021, China.
College of Life Sciences, Jilin University, Changchun, 130021, China.
Apoptosis. 2018 Feb;23(2):132-142. doi: 10.1007/s10495-018-1443-1.
In this study, a peptide-peptide co-administration therapy between hybrid peptide kla-TAT and cationic anticancer peptide HPRP-A1 was designed to increase the anticancer activity of the combination peptides through synergistic effect. kla is a pro-apoptotic peptide which could induce rapid cancer cell apoptosis by disruption the mitochondrial membrane when internalized the cells. To enhance more kla peptides pass through cell membrane, a double improvement strategy was designed by chemically conjugation with cell penetration peptide TAT as well as co-administration with cationic membrane active peptide HPRP-A1, and the double anticancer mechanism of the kla-TAT peptide and HPRP-A1 including membrane disruption and apoptosis induction was verified through in vitro experiments. The CompuSyn synergism/antagonism analysis showed that kla-TAT acted synergistically with HPRP-A1 against a non-small cell lung cancer (NSCLC) A549 cell line. The anticancer activities of the two peptides were dramatically increased by co-administration, under the mechanism of cell membrane disruption, caspase-dependent apoptosis induction, as well as cyclin-D1 down-regulation based G1 phase arrest. We believe that the synergic therapeutic strategy would be a meaningful method for the anticancer peptides used in cancer treatment.
在这项研究中，设计了一种混合肽 kla-TAT 和阳离子抗癌肽 HPRP-A1 之间的肽-肽联合给药疗法，通过协同作用提高组合肽的抗癌活性。kla 是一种促凋亡肽，当被细胞内化时，通过破坏线粒体膜诱导癌细胞快速凋亡。为了增强更多的 kla 肽穿过细胞膜，通过化学偶联细胞穿透肽 TAT 以及与阳离子膜活性肽 HPRP-A1 联合给药进行了双重改进策略，并且 kla-TAT 肽和 HPRP-A1 的双重抗癌机制通过体外实验进行了验证，包括膜破坏和凋亡诱导。CompuSyn 协同/拮抗分析表明，kla-TAT 与 HPRP-A1 对非小细胞肺癌 (NSCLC) A549 细胞系表现出协同作用。两种肽的协同给药极大地提高了它们的抗癌活性，其机制是细胞膜破坏、半胱天冬酶依赖性凋亡诱导以及基于细胞周期蛋白 D1 下调的 G1 期阻滞。我们相信，协同治疗策略将为用于癌症治疗的抗癌肽提供一种有意义的方法。
