n-(4-(n-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acrylamide and Breast-Neoplasms

The induction of necroptosis, a form of caspase-independent cell death, represents one of the most promising anticancer therapeutic modalities, as necroptosis serves as an alternative way to eliminate apoptosis-resistant tumor cells. Here, we investigated whether protein-bound polysaccharides (PBPs) derived from the fungus. PBPs showed effective antitumor activity against MCF-7 and SKMel-188 cells. Cotreatment of the cells with Nec-1, GSK'872 or NSA abrogated PBP-induced cell death, and the cells were protected against membrane rupture. Moreover, breast cancer cell death caused by PBPs was mediated by induced activation of the TNF-α/TNFR1 pathway. Interestingly, the melanoma cells did not express TNF-α or TNFR1 after PBP stimulation; instead, PBPs triggered intracellular ROS generation, which was partially diminished by the inhibitors Nec-1, GSK'872 and NSA.. These results suggest that PBPs from the fungus CV induce RIPK1/RIPK3/MLKL-mediated necroptosis in breast cancer and melanoma cells, providing novel insights into the molecular effects of PBPs on cancer cells.

Topics: Acrylamides; Benzothiazoles; Breast Neoplasms; Cell Survival; Female; Humans; Imidazoles; Indoles; MCF-7 Cells; Melanoma, Amelanotic; Necroptosis; NIMA-Related Kinase 1; Polysaccharides; Protein Kinases; Quinolines; Reactive Oxygen Species; Receptor-Interacting Protein Serine-Threonine Kinases; Receptors, Tumor Necrosis Factor, Type I; Sulfonamides; Tumor Necrosis Factor-alpha