Chromomycins A2 and A3 from Marine Actinomycetes with TRAIL Resistance-Overcoming and Wnt Signal Inhibitory Activities

摘要

A biological screening study of an actinomycetes strain assembly was conducted using a cell-based cytotoxicity assay. The CKK1019 strain was isolated from a sea sand sample. Cytotoxicity-guided fractionation of the CKK1019 strain culture broth, which exhibited cytotoxicity, led to the isolation of chromomycins A2 (>1) and A3 (>2). >1 and >2 showed potent cytotoxicity against the human gastric adenocarcinoma (AGS) cell line (IC50 >1; 1.7 and >2; 22.1 nM), as well as strong inhibitory effects against TCF/β-catenin transcription (IC50 >1; 1.8 and >2; 15.9 nM). >2 showed the ability to overcome tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) resistance. To the best of our knowledge, the effects of chromomycins A2 (>1) and A3 (>2) on TRAIL resistance-overcoming activity, and on the Wnt signaling pathway, have not been reported previously. Thus, >1 and >2 warrant potential drug lead studies in relation to TRAIL-resistant and Wnt signal-related diseases and offer potentially useful chemical probes for investigating TRAIL resistance and the Wnt signaling pathway.