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BACKGROUND: Necroptosis inhibitors, including necrostatin-1 (Nec-1), are attracting attention as potential therapeutic agents against various diseases, such as acute lung injury, chronic obstructive pulmonary disease, acute kidney injury, nonalcoholic fatty liver, and neurodegenerative disease, where necroptosis is thought to act as a contributing factor. Nec-1 suppresses necroptosis by inhibiting receptor-interacting protein (RIP) 1 kinase and can also reduce reactive oxygen species (ROS) production; however, the underlying molecular mechanisms mediating ROS reduction remain unclear. METHODS: The antioxidant effects of necroptosis inhibitors, including Nec-1 and apoptosis inhibitors, were quantified by performing a 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay. Nec-1-related compounds were subsequently assayed for cupric ion-reducing capacity and superoxide dismutase (SOD)-like activity. RESULTS: Considering all examined apoptosis and necroptosis inhibitors, Nec-1and Nec-1i exhibited antioxidant activity in DPPH radical scavenging assay. In the cupric ion-reducing capacity assay, Nec-1i showed stronger antioxidant capacity than Nec-1. In the SOD-like activity assay, both Nec-1 and Nec-1i were found to have stronger antioxidant capacity than ascorbic acid (IC50 = 4.6 ± 0.040 and 61 ± 0.54 µM, respectively). CONCLUSION: These results suggest that Nec-1 and Nec-1i may exhibit direct radical scavenging ability against superoxide anions, independent of RIP1 inhibition.

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BACKGROUND: Anisomycin, a potential anticancer therapeutic drug, exerts an antitumor effect on melanoma cells at a lower concentration than that required for other cancer cells. However, the molecular mechanisms remain unclear. MATERIALS AND METHODS: The sensitivity to and cytotoxicity of anisomycin, as well as the effects of anisomycin on glucose metabolism and relative mRNA expression of senescence- and cancer-associated genes, were studied using B16 mouse melanoma cells. RESULTS: The viability of anisomycin-treated cells decreased in a concentration-dependent manner, and the growth of cell spheroids was suppressed by 50 nM anisomycin. Glucose metabolism was reduced by anisomycin treatment, and the mRNA expression of genes responsible for growth inhibition, such as p21, p53 and Txnip was upregulated. CONCLUSION: The results suggest that anisomycin may be a promising future anticancer drug that is effective at low concentrations against melanoma by reducing glucose metabolism, causing cell senescence-like phenomena.

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Anisomycin is used as a chemical compound that possesses c-Jun N-terminal kinase (JNK)-activating effects. Recently, the potent anti-tumor effects of anisomycin have received much attention. In addition to its JNK-activating effects, anisomycin has been reported to affect gene expression in osteosarcoma, leukemia, hepatocellular carcinoma, ovarian cancer and other cancers. We previously demonstrated that anisomycin induced the degradation of transcription factor GATA-6 in DLD-1 cells (a colorectal cancer cell line) and inhibited their proliferation. However, the details of the gene network involved in the process remain unclear. In this study, we conducted an RNA-seq analysis of differentially expressed genes (DEGs) in anisomycin-treated DLD-1 cells to identify the molecular process of growth-suppressive genes. We found that LAMB3, which regulates cell adhesion and migration, and NFKB2 were down-regulated by anisomycin. In addition, the mRNA expression of several tumor suppressor genes (ATF3, ERRFI1, KLF6, and AKAP12) was transiently enhanced at 3 h after anisomycin treatment. These results suggest that anisomycin blocks a PI3K/Akt-signaling cascade to lead to the suppression of cell growth.