Abstract
Cancer has always been one of the most common malignant diseases in the world. Therefore, there is an urgent need to find potent agents with selective antitumor activity against cancer cells. It has been reported that antimicrobial peptides (AMPs) can selectively target tumor cells. In this study, we focused on the anti-tumor activity and mechanism of Brevivin-1RL1, a cationic α-helical AMP isolated from frog Rana limnocharis skin secretions. We found that Brevivin-1RL1 preferentially inhibits tumor cells rather than non-tumor cells with slight hemolytic activity. Cell viability assay demonstrated the intermolecular disulfide bridge contributes to the inhibitory activity of the peptide as the antitumor activity was abolished when the disulfide bridge reduced. Further mechanism studies revealed that both necrosis and apoptosis are involved in Brevivin-1RL1 mediated tumor cells death. Moreover, Brevivin-1RL1 induced extrinsic and mitochondria intrinsic apoptosis is caspases dependent, as the pan-caspase inhibitor z-VAD-FMK rescued Brevinin-1RL1 induced tumor cell proliferative inhibition. Immunohistology staining showed Brevivin-1RL1 mainly aggregated on the surface of the tumor cells. These results together suggested that Brevivin-1RL1 preferentially converges on the cancer cells to trigger necrosis and caspase-dependent apoptosis and Brevivin-1RL1 could be considered as a pharmacological candidate for further development as anti-cancer agent.
Highlights
Great progress has been made in the treatment of cancer in recent years [1,2,3], traditional therapies still have many defects and problems, such as widespread side effects due to non-adequate specificity for tumor cells and the tendency to develop multiple drug resistance, which greatly limit their therapeutic efficacy [4,5]
Brevinin-1RL1 is composed of 24 amino acids and it contains an intermolecular disulfide bridge consisting of seven amino acid residues at the C-terminus of the peptide
The HPLC chromatogram and mass spectrometry (MS) of fluorescein isothiocyanate (FITC) labeled Brevinin-1RL1 are shown in Supplementary Materials Figure S1a,b, respectively
Summary
Great progress has been made in the treatment of cancer in recent years [1,2,3], traditional therapies still have many defects and problems, such as widespread side effects due to non-adequate specificity for tumor cells and the tendency to develop multiple drug resistance, which greatly limit their therapeutic efficacy [4,5]. Antimicrobial peptides (AMPs), referred to as host defense peptides, have been isolated and characterized from a wide variety of organisms, such as microorganisms, insects, plants, birds, fish, amphibians and mammals, including humans, where they play an important role in the innate defense against microbial and viral invasions [6,7]. As more natural-source peptides have been discovered, other biological activities of these peptides have been explored, such as anti-fungal, anti-viral and immune regulation, as well as anti-cancer activities [8,11]. Numerous naturally derived AMPs inhibit cancer cells mainly through plasma membrane disruption or non-membranolytic cytotoxicity [12]. FK-16 derived from LL-37 could induce tumor cell death by activating non-caspase-dependent apoptosis and autophagy [22]. We disclosed that Brevinin-1RL1 preferential cytotoxicity for tumor cells to induce necrosis and caspase-dependent apoptosis to suppress tumor growth. Our study revealed the application of Brevinin-1RL1 as a potential candidate antitumor agent, and further confirmed the possibility of AMPs as a promising anticancer drug
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