Imamura Yuko, Yukawa Masashi, Kimura Ken-ichi, Takahashi Hidetoshi, Suzuki Yoshihiro, Ojika Makoto, Sakagami Youji, Tsuchiya Eiko
Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Japan.
Biosci Biotechnol Biochem. 2005 Nov;69(11):2213-8. doi: 10.1271/bbb.69.2213.
Fredericamycin A (FMA) is an antibiotic product of Streptomyces griseus that exhibits modest antitumor activity in vivo and in vitro, but, its functions in vivo are poorly understood. We identified this compound as an inducer of G1 arrest in the yeast, Saccharomyces cerevisiae. FMA exhibits an IC50 of 24 nM towards the growth of a disruptant of multi-drug resistance genes, W303-MLC30, and its cytotoxicity is a function of the time of exposure as well as drug dose. Addition of 0.8 microM of FMA caused aggregation of mitochondria within 10 min of incubation and the drug induced petites at high frequency after 4 h of incubation. Rho(-) cells were about 20 times more resistant to FMA than isogenic rho(+) cells. Overexpression of topoisomerase I, a previously suggested target of the drug, did not alleviate the sensitivity of the cells to FMA or the aggregation of mitochondria. Our results suggest that mitochondria are the primary target site of FMA.
弗雷德里卡霉素A（FMA）是灰色链霉菌产生的一种抗生素产品，在体内和体外均表现出适度的抗肿瘤活性，但其在体内的功能尚不清楚。我们将该化合物鉴定为酿酒酵母中G1期阻滞的诱导剂。FMA对多药耐药基因破坏株W303-MLC30的生长表现出24 nM的IC50，其细胞毒性是暴露时间和药物剂量的函数。添加0.8 microM的FMA在孵育10分钟内导致线粒体聚集，并且在孵育4小时后该药物高频诱导小菌落。Rho(-)细胞对FMA的抗性比同基因的Rho(+)细胞高约20倍。先前认为是该药物靶点的拓扑异构酶I的过表达并未减轻细胞对FMA的敏感性或线粒体的聚集。我们的结果表明线粒体是FMA的主要靶点。
