Abstract
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.
Highlights
Natural small molecules from actinomycetes provide a number of antimicrobials and anticancer agents with original and ingenious structures, as well as strong biological activities [1]
We recently examined the active constituents in the fermented broth of the actinomycetes strain, CKK1019, which led to the isolation of chromomycins A2 (1) and A3 (2) as bioactive compounds
Using a cell-based cytotoxicity assay system, we examined the extracts of actinomycetes isolated and cultivated in our laboratory and detected the cytotoxic effects against the human gastric adenocarcinoma (AGS) cell line (34% viability of the control at 10 μg/mL) of the MeOH extract of the
Summary
Natural small molecules from actinomycetes provide a number of antimicrobials and anticancer agents with original and ingenious structures, as well as strong biological activities [1] As a result, they are widely recognized as a promising resource that can potentially supply new drug discovery lead or seed compounds. We have previously isolated actinomycetes from soil, sea sand and seawater samples collected around Japan in order to investigate the bioactive metabolites obtained from these actinomycetes. In our screening program for obtaining bioactive natural products from our actinomycetes assembly, which consists of more than 1200 strains, we detected several strains that showed potent cytotoxicity Of these strains, we recently examined the active constituents in the fermented broth of the actinomycetes strain, CKK1019, which led to the isolation of chromomycins A2 (1) and A3 (2) as bioactive compounds. We will describe the activity-guided isolation and identification of those active compounds
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