Abstract
Venoms of cobras (Naja spp.) contain high abundances of cytotoxins, which contribute to tissue necrosis in cobra envenomation. The tissue-necrotizing activity of cobra cytotoxins, nevertheless, indicates anticancer potentials. This study set to explore the anticancer properties of the venoms and cytotoxins from Naja sumatrana (equatorial spitting cobra) and Naja kaouthia (monocled cobra), two highly venomous species in Southeast Asia. The cytotoxicity, selectivity, and cell death mechanisms of their venoms and cytotoxins (NS-CTX from N. sumatrana: NS-CTX; N. kaouthia: NK-CTX) were elucidated in human lung (A549), prostate (PC-3), and breast (MCF-7) cancer cell lines. Cytotoxins were purified through a sequential fractionation approach using cation-exchange chromatography, followed by C18 reverse-phase high-performance liquid chromatography (HPLC) to homogeneity validated with sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and identified by liquid chromatography-tandem mass spectrometry (LCMS/MS). The cobra venoms and their respective cytotoxins exhibited concentration-dependent growth inhibitory effects in all cell lines tested, with the cytotoxins being more potent compared to the corresponding whole venoms. NS-CTX and NK-CTX are, respectively, P-type and S-type isoforms of cytotoxin, based on the amino acid sequences as per LCMS/MS analysis. Both cytotoxins exhibited differential cytotoxic effects in the cell lines tested, with NS-CTX (P-type cytotoxin) being significantly more potent in inhibiting the growth of the cancer cells. Both cytotoxins demonstrated promising selectivity only for the A549 lung cancer cell line (selectivity index = 2.17 and 2.26, respectively) but not in prostate (PC-3) and breast (MCF-7) cancer cell lines (selectivity index < 1). Flow cytometry revealed that the A549 lung cancer cells treated with NS-CTX and NK-CTX underwent necrosis predominantly. Meanwhile, the cytotoxins induced mainly caspase-independent late apoptosis in the prostate (PC-3) and breast (MCF-7) cancer cells lines but lacked selectivity. The findings revealed the limitations and challenges that could be faced during the development of new cancer therapy from cobra cytotoxins, notwithstanding their potent anticancer effects. Further studies should aim to overcome these impediments to unleash the anticancer potentials of the cytotoxins.
Highlights
Cancer is a disease characterized by abnormal and uncontrollable cell division
The venoms of N. sumatrana (NS) and N. kaouthia (NK) exhibited concentration-dependent cytotoxic activities toward the three cancer cell lines tested, with varying half maximal inhibitory concentrations (IC50) (Supplementary File S1). Both cobra venoms were most potent in inhibiting the growth of lung cancer cell line (A549, IC50 = 2.21-3.26 μg/ml), moderately cytotoxic to the prostate cancer cell line (PC-3, IC50 = 5.589.88 μg/ml), and least cytotoxic toward breast cancer cell line (MCF-7, IC50 = 10-34.47 μg/ml) (Supplementary File S2)
N. sumatrana venom showed a wide range of cytotoxicity across the three cell lines, where the growths of A549 and PC-3 were significantly inhibited 6–15 times more potently than MCF-7 (A549: IC50 = 2.21 ± 0.25 μg/ml; PC-3: IC50 = 5.58 ± 0.67 μg/ml; MCF-7: IC50 = 34.47 ± 1.59 μg/ml) (p < 0.001)
Summary
Cancer is a disease characterized by abnormal and uncontrollable cell division. It has become the second leading cause of death globally, with 9.6 million deaths reported by the WHO in 2018 (Bray et al, 2018). The pursuit for a cancer-specific, non-resistant, and potent compound has been the cornerstone in anticancer drug discovery (Liberio et al, 2013). In this context, snake venom proteins are promising candidates for novel anticancer agents (Li et al, 2018). The mammalian system-targeting property of snake venom proteins is typically specific and selective, making them a repertoire of bioactive molecules for the discovery of new therapeutic agents (Lewis and Garcia, 2003)
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