Anticancer activity of a synthetic peptide derived from harmoniasin, an antibacterial peptide from the ladybug Harmonia axyridis

Abstract

Abstract.Harmoniasin is a defensin-like antimicrobial peptide identified from the ladybug Harmonia axyridis. Among the synthetic homodimer peptide analogues derived from harmoniasin, HaA4 has been found to have antibacterial activity without hemolytic activity. In this study, we investigated whether HaA4 has anticancer activity against human leukemia cell lines such as U937 and Jurkat cells. HaA4 manifested cytotoxicity and decreased the cell viability of U937 and Jurkat cells in MTS assay and LDH release assay. We found that HaA4 induced apoptotic and necrotic cell death of the leukemia cells using flow cytometric analysis, acridine orange/ethidium bromide staining and nucleosomal fragmentation of genomic DNA. Activation of caspase-7 and -9 and fragmentation of poly (ADP-ribose) polymerase was detected in the HaA4-treated leukemia cells, suggesting induction of a caspase-dependent apoptosis pathway by HaA4. Caspase-dependent apoptosis was further confirmed by reversal of the HaA4-induced viability reduction by treatment of Z-VAD-FMK, a pan-caspase inhibitor. In conclusion, HaA4 caused necrosis and caspase-dependent apoptosis in both U937 and Jurkat leukemia cells, which suggests potential utility of HaA4 as a cancer therapeutic agent.

The antimicrobial peptide pardaxin exerts potent anti-tumor activity against canine perianal gland adenoma

“…Induction of necrosis has been a consistent finding in previous studies of the effects of antimicrobial peptide on cancer, including studies of animals with solid tumors [ 12 , 31 ]. Our earlier findings suggest pardaxin triggers apoptotic signaling pathways in human cervical carcinoma HeLa cells [ 27 ], consistent with findings that other antimicrobial peptides induce caspase-dependent apoptosis or programmed cell death of cancer cells via both mitochondrial and death receptor pathways [ 32 , 33 ]. However, our observation of vacuolation at injected tumor sites in dogs suggests that pardaxin may interact with negatively-charged plasma membranes, causing their disintegration [ 34 , 35 ].…”

Peptides with Dual Antimicrobial–Anticancer Activity: Strategies to Overcome Peptide Limitations and Rational Design of Anticancer Peptides

“…The details of tests done on peptides with dual antimicrobial–anticancer activity are given in Table 2 . Some of these tests are antimicrobial activity, hemolytic activity, cytotoxicity tests on tumor cells, live imaging, Western blotting, DNA fragmentation tests, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, anti-angiogenesis assay, flow cytometry, release of lactate dehydrogenase (LDH), reactive oxygen intermediates (ROS) assay, analysis of morphological changes by hematoxylin-eosin (H/E) staining, and P-glycoprotein (Pgp) sensitivity assay [ 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ].…”

Insect antimicrobial peptides: potential tools for the prevention of skin cancer

“…Anionic molecules (phosphatidylserines, glycoproteins, glycosaminoglycans, heparan sulfate, O -glycosylated mucins, and sialylated gangliosides) confer a net negative charge on the membranes of cancer cells, in contrast to the typically zwitterionic membranes of normal cells (Giuliani et al 2007 ; Hoskin and Ramamoorthy 2008 ; Raz et al 1980 ; Schweizer 2009 ; Utsugi et al 1991 ). The mode of action may involve electrostatic interactions between cationic peptides and the anionic components of cancer cell membranes (Kim et al 2013 ). The same “carpet-like” and “barrel-stave” models that explain the interaction between AMPs and bacterial membranes can therefore also be invoked to describe interactions with cancer cells (Oren and Shai 1998 ; Pouny and Shai 1992 ; Schweizer 2009 ).…”

“…Alloferon 1 isolated from bacteria-challenged larvae of the blow fly Calliphora vicina was able to stimulate NK cell activity and interferon (IFN) synthesis in animal and human models and could enhance antiviral and antitumor activity in mice (Chernysh et al 2002 ). The harmoniasin analog HaA4 was found to be cytotoxic toward human leukemia cell lines such as U937 and Jurkat cells by inducing both caspase-dependent apoptosis and necrosis (Kim et al 2013 ). D-peptides A, B, C, and D, designed and synthesized based on the sequences of 43-mer defensins from two beetles, were able to inhibit the growth of several cancer cell lines with different levels of efficacy, and D-peptide B showed the most selective activity against the mouse myeloma cell line P3-X63-Ag8.653.…”

“…Such peptides are produced naturally by nearly all organisms as a part of the innate immune system (Rahnamaeian et al 2016 ; Tonk et al 2014 ), and due to their broad antimicrobial spectrum, they are often described as natural antibiotics (Bolouri Moghaddam et al 2015 ). Several insect AMPs also show cytotoxic effects against diverse cancer cell lines, such as mouse myeloma, melanoma, lymphoma, leukemia, breast cancer, and lung cancer (Iwasaki et al 2009 ; Kang et al 2012 ; Kim et al 2013 ; Xiao et al 2006 ). These anticancer peptides (ACPs) are characterized by high therapeutic efficacy, a low probability of resistance emerging in target cells, and limited or no toxicity against mammalian erythrocytes, macrophages, and fibroblasts (Barbault et al 2003 ; Saido-Sakanaka et al 2004 ; Yamada et al 2005 ).…”