Effect of hydrophobicity on distinct anticancer mechanism of antimicrobial peptide chensinin-1b and its lipoanalog PA-C1b in breast cancer cells.

Abstract

Chensinin-1b and its lipoanalogs demonstrate different anticancer activities against selected cancer cells, and the anticancer activity of PA-C1b is improved up to 3-fold compared with that of the parent peptide chensinin-1b. However, detailing the mechanism of action of these peptides is required to better understand the structure-function relationship. In this study, chensinin-1b and PA-C1b were selected as the representative peptides to investigate the mode of action in cancer cells. The results indicated that the boundary of the cell membrane was broken when the cells were treated with chensinin-1b, while that of cells treated with PA-C1b remained intact based on morphological changes. Apoptosis assays indicated that PA-C1b induced MCF-7 cancer cell apoptosis, while chensinin-1b mainly damaged the cell membrane. MCF-7 cancer cells treated with the peptides induced the loss of mitochondrial membrane potential, and cytochrome c was released from mitochondria, but PA-C1b enhanced ROS generation. Additionally, PA-C1b uptake occurred via an energy-dependent pathway and was inhibited by selected endocytosis inhibitors. Furthermore, treatment of MCF-7 cells with PA-C1b suppressed Bcl-2 mRNA levels and increased Bax mRNA levels, upregulated the expression of the proapoptotic protein Bax and downregulated the expression of the antiapoptotic protein Bcl-2. These results indicate that the anticancer mechanism of AMPs may be considerably affected by only a slight difference in the hydrophobicity of the two peptides; and such a study may facilitate the design of novel peptide-based anticancer agents.