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Oral JS-38, a metabolite from Xenorhabdus sp., has both anti-tumor activity and the ability to elevate peripheral neutrophils

Min-Yu LIU, Lin XIAO, Geng-Hui CHEN, Yong-Xiang WANG, Wei-Xia XIONG, Fei LI, Ying LIU, Xiao-Ling HUANG, Yi-Fang DENG, Zhen ZHANG, Hai-Yan SUN, Quan-Hai LIU, Ming YIN
Chinese journal of natural medicines 2014 v.12 no.10 pp. 768-776
Oriental traditional medicine, Xenorhabdus, allografting, animal models, antineoplastic activity, apoptosis, body weight, cell lines, cyclophosphamide, fluorouracil, granulocyte colony-stimulating factor, hepatoma, humans, inhibitory concentration 50, lung neoplasms, metabolites, mice, neoplasm cells, neutropenia, neutrophils, sarcoma
JS-38 (mitothiolore), a synthetic version of a metabolite isolated from Xenorhabdus sp., was evaluated for its anti-tumor and white blood cell (WBC) elevating activities.These anti-proliferative activities were assessed in vitro using a panel of ten cell lines. The anti-tumor activities were tested in vivo using B16 allograft mouse models and xenograft models of A549 human lung carcinoma and QGY human hepatoma in nude mice. The anti-tumor interactions of JS-38 and cyclophosphamide (CTX) or 5-fluorouracil (5-Fu) were studied in a S180 sarcoma model in ICR mice. Specific stimulatory effects were determined on peripheral neutrophils in normal and CTX- and 5-Fu-induced neutropenic mice.The IC50 values ranged from 0.1 to 2.0 μmol·L⁻¹. JS-38 (1 μmol·L⁻¹) caused an increase in A549 tumor cell apoptosis. Multi-daily gavage of JS-38 (15, 30, and 60 mg·kg⁻¹·d⁻¹) inhibited in vivo tumor progression without a significant effect on body weight. JS-38 additively enhanced the in vivo anti-tumor effects of CTX or 5-Fu. JS-38 increased peripheral neutrophil counts and neutrophil rates in normal BALB/c mice almost as effectively as granulocyte colony-stimulating factor (G-CSF). In mice with neutropenia induced by CTX or 5-Fu, JS-38 rapidly restored neutrophil counts.These results suggest that JS-38 has anti-tumor activity, and also has the ability to increase peripheral blood neutrophils.