Abstract
Virtually all snake venoms are capable of inducing cytotoxicity, causing cell necrosis and/or apoptosis at varying degrees. Snake venom cytotoxicity manifests clinically as local necrosis, hemolysis, cardiotoxicity, myonecrosis, kidney injury and so on, either through direct mechanism or in combination with other pathogenic activities of the venom. Cytotoxins (CTXs), first discovered in cobra (genus: Naja) venoms, are the most established cytotoxic component of venom. They are single-chain polypeptides of 59-61 amino acids arranged in a three-finger fold made of anti-parallel β-strands, fortified by 4 disulfide bonds and numerous hydrogen bonds. CTXs are basic proteins with hydrophobic three-finger loops, which extremities are flanked by cationic residues (mainly lysine and arginine). The hydrophobic termini impart the amphilicity of CTXs, mediating their binding and insertion into anionic phospholipid membranes that leads to deleterious cellular events such as pore formation and lysis, increased intracellular Ca2+ ion influx and membrane depolarization, and importantly internalization of the toxin leading to mitochondrial and lysosomal damages, and the disturbances of cellular cascades resulting in cell death. Another toxin known for potent cytotoxicity is snake venom enzyme L-amino acid oxidases (LAAOs), which induce apoptosis but trigger tissue necrosis at high concentration through the liberation of hydrogen peroxide. LAAOs are likely the principal cytotoxic component in king cobra’s venom that causes extensive tissue necrosis, since the venom is known to contain a negligible amount of cytotoxin but exceptionally abundant LAAOs. Another ubiquitous venom enzyme, phospholipase A 2 (PLA 2 ), is also known to cause cytotoxicity. The β-neurotoxic PLA2s involves phospholipid hydrolysis of neuronal membrane, while non-catalytic Lys49-PLA 2 s display myotoxicity through membrane disrupting action brought by its cationic C-terminus. Besides, venom enzymes like PLA 2 s or snake venom metalloproteases (SVMPs) are also toxic to cause complications like hemolysis and renal cell death in envenomation. Successful treatment of envenomation hence should entail the arrest of cytotoxicity, which is possible with the use of appropriate antivenom that neutralizes the cytotoxic components in circulation, although the outcome on treating local cytotoxicity is often less satisfactory. On the other hand, cytotoxic components from venoms are pharmacologically active molecules that can be explored for therapeutic uses. In recent years, compounds like CTXs, LAAOs, PLA 2 , SVMPs, disintegrins, Kunitz-type serine inhibitors and snaclecs sourced from venoms have been widely investigated for their antineoplastic potentials. Recent advents in toxin profiling (venomics) and purification, molecular cloning, transcriptomics and cell-based assays have contributed greatly to unveiling the complexity of toxins in venoms, thereby deepening the knowledge of venom diversity, broadening insights into the pathogenesis of venom cytotoxicity and enriching the reservoir of toxins available for therapeutic application.