Brevinin‐2R¹ semi‐selectively kills cancer cells by a distinct mechanism, which involves the lysosomal‐mitochondrial death pathway

Abstract

Brevinin-2R is a novel non-hemolytic defensin that was isolated from the skin of the frog Rana ridibunda. It exhibits preferential cytotoxicity towards malignant cells, including Jurkat (T-cell leukemia), BJAB (B-cell lymphoma), HT29/219, SW742 (colon carcinomas), L929 (fibrosarcoma), MCF-7 (breast adenocarcinoma), A549 (lung carcinoma), as compared to primary cells including peripheral blood mononuclear cells (PBMC), T cells and human lung fibroblasts. Jurkat and MCF-7 cells overexpressing Bcl2, and L929 and MCF-7 over-expressing a dominant-negative mutant of a pro-apoptotic BNIP3 (ΔTM-BNIP3) were largely resistant towards Brevinin-2R treatment. The decrease in mitochondrial membrane potential (ΔΨm), or total cellular ATP levels, and increased reactive oxygen species (ROS) production, but not caspase activation or the release of apoptosis-inducing factor (AIF) or endonuclease G (Endo G), were early indicators of Brevinin-2R-triggered death. Brevinin-2R interacts with both early and late endosomes. Lysosomal membrane permeabilization inhibitors and inhibitors of cathepsin-B and cathepsin-L prevented Brevinin-2R-induced cell death. Autophagosomes have been detected upon Brevinin-2R treatment. Our results show that Brevinin-2R activates the lysosomalmitochondrial death pathway, and involves autophagy-like cell death.

Studies on Mechanism of Action of Anticancer Peptides by Modulation of Hydrophobicity Within a Defined Structural Framework

“…The peptide D-K 6 L 9 exhibits selective cytotoxicity attributed to its electrostatic interaction with surface-exposed phosphatidylserine in cancer cells (5). Brevinin-2R activates the lysosomal-mitochondrial death pathway and involves autophagy-like cell death (6). From numerous structure/activity studies on both natural and synthetic anticancer peptides, a number of factors believed to be important for anticancer activity have been identified, including hydrophobicity, net charge, amphipathicity, secondary structure in membrane, and oligomerization ability (1,7,8).…”

Scorpion venom as antimicrobial peptides (AMPs): A review article

“…Because of the structural and chemical nature diversity of AMPs, also the probability of microbes to resist AMPs is much lower than conventional antibiotics, make them a good candidate for a novel drug with anti bacterial, anti fungal and anti viral properties [48,49]also Anti parasitic activity [50] and AMPs may used in treatment of cancer [51,52,53] and HIV infections [54].…”

Role of autophagy in the progression and suppression of leukemias

“…Some triterpenoid derivatives, novel anticancer drug candidates, were shown to induce autophagic death in CML cells by causing mitochondritoxicity [79]. Brevinin-2R, one type of defensin isolated from the skin of frog Rana ridibunda, kills T-cell leukemia and B-cell lymphoma cells selectively through autophagy, again with the involvement of mitochondria [80]. Some novel quinolinelike molecules with anti-cancer potential were also found to be important for initiation of autophagy.…”