Suppression of human prostate tumor growth in mice by a cytolytic D-, L-amino acid peptide: Membrane lysis, increased necrosis, and inhibition of prostate-specific antigen secretion

Niv Papo, Amir Braunstein, Zelig Eshhar, Yechiel Shai

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

Abstract

Gene-encoded host defense peptides are used as part of the innate immunity, and many of them act by directly lysing the cell membrane of the pathogen. A few of these peptides showed anticancer activity in vitro but could not be used in vivo because of their inactivation by serum. We designed a 15-amino acid peptide, composed of D- and L-amino acids (diastereomer), which targets both androgen-independent and androgen-dependent human prostate carcinoma cell lines (CL1, 22RV1, and LNCaP). Most importantly, we observed a complete arrest of growth in CL1 and 22RV1 xenografts treated intratumorally with the diastereomer. This was also accompanied by a lowering of prostate-specific antigen serum levels secreted by the 22RV1 xenograft. Furthermore, the diastereomer synergized with conventional chemotherapeutics. In contrast, the parental all L-amino acids peptide was highly active only in vitro and could not discriminate between tumor and nontumor cells. Fluorescent confocal microscopy, histopathologic examination, and cell permeability studies (depolarization of transmembrane potential and release of an encapsulated dye) suggest a necrotic mechanism of killing, after a threshold concentration of peptide has been reached. Its destructive killing effect and the simple sequence of the diastereomer make it an attractive chemotherapeutic candidate possessing a new mode of action, with potential to be developed additionally for the treatment of prostate carcinoma.

Original languageEnglish
Pages (from-to)5779-5786
Number of pages8
JournalCancer Research
Volume64
Issue number16
DOIs
StatePublished - 15 Aug 2004
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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