title: Necroptosis modulated by autophagy is a predominant form of melanoma cell death induced by sanguilutine.
abstract: We show that the plant quaternary benzo[c]phenanthridine alkaloid sanguilutine (SL) is a strong inducer of caspase-independent non-apoptotic death in human melanoma cells. Necrostatin-1, a specific inhibitor of necroptosis, completely reversed the cytotoxic effect of SL, suggesting that necroptosis was a predominant type of cell death induced by SL in these cells. In addition, we showed that SL can trigger an autophagic response, as confirmed by GFP-LC3 puncta formation and LC3-II accumulation. Interestingly, we observed a significant decrease in the viability of melanoma cells treated with combination of autophagy inhibitors (3-methyladenine, bafilomycin-A1 and LY294002) and SL. Our results further indicated that autophagy may serve as a pro-survival mechanism, delaying the induction of necroptosis in melanoma cells. The ability of SL to induce caspase-independent non-apoptotic cell death (necroptosis) suggests its possible therapeutic potential in the treatment of apoptosis-resistant melanoma tumours. Furthermore, SL might serve as a useful tool for studying the mechanisms of necroptosis and autophagy induction and the interplay between these two processes.
authors.affiliation: Department of Biology, Masaryk University, Kamenice Brno, Czech Republic.
authors.forename: Jindřiška
authors.initials: J
authors.lastname: Hammerová
authors.forename: Stjepan
authors.initials: S
authors.lastname: Uldrijan
authors.forename: Eva
authors.initials: E
authors.lastname: Táborská
authors.forename: Alena Hyršlová
authors.initials: AH
authors.lastname: Vaculová
authors.forename: Iva
authors.initials: I
authors.lastname: Slaninová
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D053119:Benzophenanthridines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008545:Melanoma / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D053119:Benzophenanthridines; D007093:Imidazoles; D007211:Indoles; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C507699:necrostatin-1; C550175:sanguilutine; C025946:3-methyladenine; D020169:Caspases; D000225:Adenine