title: The anticancer effect of cytotoxin 1 from Naja atra Cantor venom is mediated by a lysosomal cell death pathway involving lysosomal membrane permeabilization and cathepsin B release.
abstract: The cytotoxin family of cobra venom proteins, also called cardiotoxins, can activate both necrotic and apoptotic cell death pathways in cancer cells. Cytotoxin 1 (CTX1)from Naja atra Cantor venom is a 60 amino acid, 6698 Da protein with as yet untested anticancer efficacy and cell selectivity. We tested the toxicity of CTX1 on a number of cancer cell lines (MCF-7, P388, K562, and H22) and on one normal human cell line (16HBE). The rank order of cytotoxicity was MCF-7 > P388 ≈ K562 >H22 ≈ 16HBE, indicating that the effect of CTX1 on certain cancer cell types was relatively selective.Treatment with CTX1 greatly prolonged the survival of P388 ascites tumors bearing KM mice compared to cyclophosphamide treatment. Cell viability, apoptosis, and lysosomal permeability assays all demonstrated that CTX1 induced dose- and time-dependent cell death, with most cells exhibiting the morphological and biochemical features of late apoptosis and necrosis. Mitochondrial membrane potential was lost in CTX1-treated P388 cells. In addition, CTX1 induced an increase in both lysosomal membrane permeability and cathepsin B protease activity. These analyses reveal that CTX1 possesses significant and selective anticancer activity, likely by inducing programmed cell death through mitochondrial and/or lysosomal pathways.
authors.affiliation: Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong 510182, China.
authors.forename: Minyan
authors.initials: M
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Ming
authors.forename: Ya
authors.initials: Y
authors.lastname: Tang
authors.forename: Shengming
authors.initials: S
authors.lastname: Zhou
authors.forename: Tianhan
authors.initials: T
authors.lastname: Kong
authors.forename: Weihua
authors.initials: W
authors.lastname: Dong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002401:Cathepsin B / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004546:Elapid Venoms / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D017815:Elapidae; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects*; D020014:K562 Cells; D007941:Leukemia P388 / Q000188:drug therapy / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects*; D061986:MCF-7 Cells; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010539:Permeability
chemical_list: D000970:Antineoplastic Agents; D004546:Elapid Venoms; C037375:cobra cytotoxin I; D003520:Cyclophosphamide; D002401:Cathepsin B