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Recently a novel defensin, Brevinin-2R, a 25-amino acid polypeptide was isolated from the skin of the frog Rana ridibunda. The novel molecule kills semi-selectively cancer cells, but does not exhibit the typical hemolytic activity for the majority of the Brevinin-family defensins. The anti-cancer activity was demonstrated on various malignant cells such as Jurkat (T-cell leukemia), BJAB (B-cell lymphoma), SW742 (colon carcinoma), and MCF-7 (breast adenocarcinoma). Also data have shown that L929 and MCF-7 cells stably transfected with a dominant-negative mutant of the pro-apoptotic Bcl-2-family member BNIP3 (DTM-BNIP3) were significantly more resistant towards Brevinin-2R triggered cell death. Furthermore, we observed decrease in mitochondrial membrane potential (ΔΨm) and that induction of cell death is independent of caspase activation. Over-expressing of Bcl-2 in cancer cell lines significantly counteracted ΔΨm triggered by Brevinin-2R. Malignant hematopoietic cell lines were more sensitive towards Brevinin-2R than primary peripheral blood mononuclear cells (PBMC). Our results demonstrate that the polypeptide leads to activation of the mitochondrial death pathway, but does not induce cell death in cancer cells by classical apoptosis. The semi-selective anti-cancer effect of Brevinin-2R makes it a promising lead molecule for the development of anti-cancer drugs.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA