Toume Kazufumi, Tsukahara Kentaro, Ito Hanako, Arai Midori A, Ishibashi Masami
Department of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Mar Drugs. 2014 Jun 5;12(6):3466-76. doi: 10.3390/md12063466.
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.
使用基于细胞的细胞毒性测定法对放线菌菌株组合进行了生物学筛选研究。CKK1019菌株是从海砂样品中分离出来的。对表现出细胞毒性的CKK1019菌株培养液进行细胞毒性导向分级分离，得到了色霉素A2（1）和A3（2）。化合物1和2对人胃腺癌（AGS）细胞系显示出强大的细胞毒性（IC50 1为1.7 nM，2为22.1 nM），并且对TCF/β-连环蛋白转录具有强烈的抑制作用（IC50 1为1.8 nM，2为15.9 nM）。化合物2显示出克服肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）抗性的能力。据我们所知，色霉素A2（1）和A3（2）对克服TRAIL抗性活性以及对Wnt信号通路的影响此前尚未见报道。因此，化合物1和2值得针对TRAIL抗性和Wnt信号相关疾病开展潜在的药物先导研究，并为研究TRAIL抗性和Wnt信号通路提供潜在有用的化学探针。
