A Novel Naphthyridine Derivative, 3u, Induces Necroptosis at Low Concentrations and Apoptosis at High Concentrations in Human Melanoma A375 Cells

Abstract

Naphthyridine derivatives are a widely-used class of heterocycles due to their pharmacological activities. A novel compound (10-Methoxy-1,2,3,4-tetrahydrobenzo(g)(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.

Keywords

• naphthyridine derivative
• death receptors
• apoptosis
• caspase-8
• necroptosis
• melanoma