Resistance to Degradation and Cellular Distribution Are Important Features for the Antitumor Activity of Gomesin

Resistance to Degradation and Cellular Distribution Are Important Features for the Antitumor Activity of Gomesin

Author Buri, Marcus Vinicius Autor UNIFESP Google Scholar
Domingues, Tatiana Moreira Autor UNIFESP Google Scholar
Paredes-Gamero, Edgar Julian Autor UNIFESP Google Scholar
Casaes-Rodrigues, Rafael L. Autor UNIFESP Google Scholar
Rodrigues, Elaine Guadelupe Autor UNIFESP Google Scholar
Miranda, Antonio Autor UNIFESP Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Abstract Many reports have shown that antimicrobial peptides exhibit anticancer abilities. Gomesin (Gm) exhibits potent cytotoxic activity against cancer cells by a membrane pore formation induced after well-orchestrated intracellular mechanisms. in this report, the replacements of the Cys by Ser or Thr, and the use D-amino acids in the Gm structure were done to investigate the importance of the resistance to degradation of the molecule with its cytotoxicity. [Thr(2,6,11,15)]-Gm, and [Ser(2,6,11,15)]-Gm exhibits low cytotoxicity, and low resistance to degradation, and after 24 h are present in localized area near to the membrane. Conversely, the use of D-amino acids in the analogue [D-Thr(2,6,11,15)]-D-Gm confers resistance to degradation, increases its potency, and maintained this peptide spread in the cytosol similarly to what happens with Gm. Replacements of Cys by Thr and Gln by L- or D-Pro ([D-Thr(2,6,11,15), Pro(9)]-D-Gm, and [Thr(2,6,11,15), D-Pro(9)]-Gm), which induced a similar beta-hairpin conformation, also increase their resistance to degradation, and cytotoxicity, but after 24 h they are not present spread in the cytosol, exhibiting lower cytotoxicity in comparison to Gm. Additionally, chloroquine, a lysosomal enzyme inhibitor potentiated the effect of the peptides. Furthermore, the binding and internalization of peptides was determined, but a direct correlation among these factors was not observed. However, cholesterol ablation, which increase fluidity of cellular membrane, also increase cytotoxicity and internalization of peptides. beta-hairpin spatial conformation, and intracellular localization/target, and the capability of entry are important properties of gomesin cytotoxicity.
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Grant number FAPESP: 2011/17584-0
Date 2013-11-29
Published in Plos One. San Francisco: Public Library Science, v. 8, n. 11, 10 p., 2013.
ISSN 1932-6203 (Sherpa/Romeo, impact factor)
Publisher Public Library Science
Extent 10
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000327670300020

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