d-Amino Acid Position Influences the Anticancer Activity of Galaxamide Analogs: An Apoptotic Mechanism Study

• Published in: International journal of molecular sciences Vol. 18; no. 3; p. 544
• Main Authors: Bai, Defa, Yu, Siming, Zhong, Shenghui, Zhao, Bingxin, Qiu, Shaoling, Chen, Jianwei, Lunagariya, Jignesh, Liao, Xiaojian, Xu, Shihai
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 10.03.2017; MDPI AG
• Subjects: ">d-amino acid; Amino Acids - chemistry; anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; cyclopeptide; Galaxamide analogs; Galaxaura; HeLa Cells; Hep G2 Cells; Humans; MCF-7 Cells; mechanism; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; mechanism; Galaxamide analogs; ">d-amino acid; cyclopeptide; anticancer
• ISSN: 1422-0067; 1422-0067
• DOI: 10.3390/ijms18030544

Galaxamide, an extract from , is a cyclic pentapeptide containing five l-leucines. Due to the particular cyclic structure and the excellent anticancer activity, synthesis of Galaxamide and its analogs and their subsequent bio-applications have attracted great attention. In the present work, we synthesized six Galaxamide analogs by replacing one of the l-leucines with phenylalanine and varying the d-amino acid position. The anticancer effect of the synthesized Galaxamide analogs was tested against four in vitro human cancer cell lines, human hepatocellular cells (HepG₂), human breast cancer cell (MCF-7), human breast adenocarcinoma cells (MDA-MB-435) and a human cervical carcinoma cell line (Hela). Results showed that Galaxamide analogs with different d-amino acid positions displayed distinct anticancer potential. The Galaxamide analog containing d-amino acid at position 5 (Analog-6) presented the strongest anticancer activity. The mechanism study revealed that Analog-6 could cause the early apoptosis of HepG₂ cells by inhibiting their growth in the sub-G1 stage of the cell cycle and induce the chromatin condensation and fragmentation, which can be seen as 68% of HepG₂ cells inhibited in the sub-G1 stage. Moreover, a mitochondria-mediated pathway was found to be involved in the apoptotic process of Analog-6 on HepG₂ cells.