Abstract
L-amino acid oxidases from snake venoms have been described to possess various biological functions. In this study, we investigated the inflammatory responses induced in vivo and in vitro by CR-LAAO, an L-amino acid oxidase isolated from Calloselasma rhodostoma venom, and its antitumor potential. CR-LAAO induced acute inflammatory responses in vivo, with recruitment of neutrophils and release of IL-6, IL-1β, LTB4 and PGE2. In vitro, IL-6 and IL-1β production by peritoneal macrophages stimulated with CR-LAAO was dependent of the activation of the Toll-like receptors TLR2 and TLR4. In addition, CR-LAAO promoted apoptosis of HL-60 and HepG2 tumor cells mediated by the release of hydrogen peroxide and activation of immune cells, resulting in oxidative stress and production of IL-6 and IL-1β that triggered a series of events, such as activation of caspase 8, 9 and 3, and the expression of the pro-apoptotic gene BAX. We also observed that CR-LAAO modulated the cell cycle of these tumor cells, promoting delay in the G0/G1 and S phases. Taken together, our results suggest that CR-LAAO could serve as a potential tool for the development of novel immunotherapeutic strategies against cancer, since this toxin promoted apoptosis of tumor cells and also activated immune cells against them.
Highlights
L-amino acid oxidases from snake venoms have been described to possess various biological functions
There was a significant increase in the concentrations of the lipid mediators LTB4 (Fig. 2C) and PGE2 (Fig. 2D) in comparison to the negative control levels. These results indicate that CR-L-amino acid oxidases (LAAOs) induced acute inflammatory responses in vivo after 4 h of stimulus, with recruitment of neutrophils resulting in increased levels of cytokines, LTB4 and PGE2
The inflammatory process promoted by snake envenomations is mainly manifested locally at the site of the bite, and the key toxins involved are phospholipases A216,17 and metalloproteases[18,19], though other toxins have been described with pro-inflammatory activity, such as serine proteases[20] and LAAOs12
Summary
L-amino acid oxidases from snake venoms have been described to possess various biological functions. We investigated the inflammatory responses induced in vivo and in vitro by CR-LAAO, an L-amino acid oxidase isolated from Calloselasma rhodostoma venom, and its antitumor potential. Our results suggest that CR-LAAO could serve as a potential tool for the development of novel immunotherapeutic strategies against cancer, since this toxin promoted apoptosis of tumor cells and activated immune cells against them. Numerous medical and scientific studies have been in search of ways to use our own immune system to confront diseases In this context, new discoveries have led to treatment strategies, known as immunotherapy, with excellent results against cancer[1,2], so much so that the American Society of Clinical Oncology elected immunotherapy as the biggest breakthrough against cancer in 20163. ® cytokine IL-2 (Proleukin ), for example, is current used in the treatment of metastatic melanoma and renal cell www.nature.com/scientificreports/
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