King Cobra (Ophiophagus hannah) Venom L-Amino Acid Oxidase Induces Apoptosis in PC-3 Cells and Suppresses PC-3 Solid Tumor Growth in a Tumor Xenograft Mouse Model

Abstract

King cobra (Ophiophagus hannah) venom L-amino acid oxidase (OH-LAAO), a heat stable enzyme, has been shown to exhibit very potent anti-proliferative activity against human breast and lung tumorigenic cells but not in their non-tumorigenic counterparts. We further examine its in vitro and in vivo anti-tumor activity in a human prostate adenocarcinoma (PC-3) model. OH-LAAO demonstrated potent cytotoxicity against PC-3 cells with IC50 of 0.05 µg/mL after 72 h incubation in vitro. It induced apoptosis as evidenced with an increase in caspase-3/7 cleavages and an increase in annexin V-stained cells. To examine its in vivo anti-tumor activity, we treated PC-3 tumor xenograft implanted subcutaneously in immunodeficient NU/NU (nude) mice with 1 µg/g OH-LAAO given intraperitoneally (i.p.). After 8 weeks of treatment, OH-LAAO treated PC-3 tumors were markedly inhibited, when compared to the control group (P <0.05). TUNEL staining analysis on the tumor sections showed a significantly increase of apoptotic cells in the LAAO-treated animals. Histological examinations of the vital organs in these two groups showed no significant differences with normal tissues, indicating no obvious tissue damage. The treatment also did not cause any significant changes on the body weight of the mice during the duration of the study. These observations suggest that OH-LAAO cytotoxic effects may be specific to tumor xenografts and less to normal organs. Given its potent anti-tumor activities shown in vitro as well as in vivo, the king cobra venom LAAO can potentially be developed to treat prostate cancer and other solid tumors.

l-amino acid oxidase from Bothrops marajoensis causes nephrotoxicity in isolated perfused kidney and cytotoxicity in MDCK renal cells

“…The apoptotic effect of LAAOs from snake venoms has been reported by many authors, such as Lee et al (2014), Samel et al (2006), Zhang et al (2004), Alves et al (2008) and Ande et al (2008).…”

“…Re-oxidation of FAD by molecular O 2 results, in turn, in the production of keto acids, ammonia and hydrogen peroxide (H 2 O 2 ) (Moustafa et al, 2006;Tan and Fung, 2009). The generated H 2 O 2 can induce (St abeli et al, 2004) and inhibit platelet aggregation (Sakurai et al, 2003;Naumann et al, 2011), induce endothelial injury (Du and Clemetson, 2002) and are involved in the apoptosis of various cell cells due to DNA damage Marcussi et al, 2013;Lee et al, 2014). Bothrops marajoensis is found in the plains of Maraj o Island in the State of Par a, Brazil and possibly along the coastal lowlands of the Amazon Delta, in Brazil (Cavalcante et al, 2011).…”

Cytotoxicity of Bothrops pauloensis Venom on Madin-Darby Canine Kidney Cells: Cell Death Mechanism

“…The results indicated an apparent membrane rupture in MDCK cells at the highest concentrations studied ( Figure 1B), showing an increase in LDH release. Apoptosis caused by snake venoms is mediated by various different components, such as metalloprotease, phospholipase A2 and L-amino acid oxidase [4][5][6][7][8]. Several studies have confirmed the involvement of Bothrops and Bothropoides venom components in apoptosis [9,10].…”

Therapeutic Uses of Amino Acids

“…In a study of the king cobra (Ophiophagus hannah) venom l-amino acid oxidase, Lee et al [32] reported that the heat-stable enzyme exhibited very potent anti-proliferative activity against human breast and lung tumorigenic cells, but not in their non-tumorigenic counterparts. They further reported that after eight weeks of treatment of mice samples with the isolated LAAOs, the enzyme markedly inhibited PC-3 tumours when compared to the control group.…”