Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China.
Faculty of Enviromental Science and Engineering, Kunming University of Science and Technology, Kunming 650500, China.
Int J Mol Sci. 2018 Sep 29;19(10):2975. doi: 10.3390/ijms19102975.
Naphthyridine derivatives are a widely-used class of heterocycles due to their pharmacological activities. A novel compound (10-Methoxy-1,2,3,4-tetrahydrobenzo()(1,3) diazepino(1,2-a)-(1,8)naphthyridin-6-yl)(phenyl) methanone (named 3u), showed good anticancer activity in the human malignant melanoma cell line A375 via Thiazolyl Blue Tetrazolium Bromide (MTT) assay. After Western blotting confirmed, we found that 3u induces necroptosis at low concentrations and apoptosis at high concentrations via the upregulation of death receptors and scaffold protein in A375 cells. Furthermore, by combining 3u with the caspase inhibitor zVAD-fmk or Receptor Interacting Serine/Threonine Kinase 1 (RIP1) kinase inhibitor Necrostatin-1 (Nec-1), we found that the activity of caspase-8 was the crucial factor that determined whether either apoptosis or necroptosis occurred. The results indicate that 3u should be considered as a potential chemical substance for melanoma treatment.
萘啶衍生物因其药理学活性而被广泛用作一类杂环化合物。一种新型化合物（10-甲氧基-1,2,3,4-四氢苯并（）（1,3）二氮杂环庚烷（1,2-a）-（1,8）萘啶-6-基）（苯基）甲酮（命名为 3u），通过噻唑蓝四唑溴盐（MTT）试验显示出对人恶性黑色素瘤细胞系 A375 的良好抗癌活性。经 Western blot 证实，我们发现 3u 通过上调 A375 细胞中的死亡受体和支架蛋白，在低浓度时诱导坏死，在高浓度时诱导凋亡。此外，通过将 3u 与半胱天冬酶抑制剂 zVAD-fmk 或受体相互作用丝氨酸/苏氨酸激酶 1（RIP1）激酶抑制剂 Necrostatin-1（Nec-1）联合使用，我们发现半胱天冬酶-8 的活性是决定发生凋亡还是坏死的关键因素。结果表明，3u 可被视为一种用于治疗黑色素瘤的潜在化学物质。
