GEX1 compounds, novel antitumor antibiotics related to herboxidiene, produced by Streptomyces sp -: II.: The effects on cell cycle progression and gene expression

被引:58
作者
Sakai, Y
Tsujita, T
Akiyama, T
Yoshida, T
Mizukami, T
Akinaga, S
Horinouchi, S
Yoshida, M
Yoshida, T
机构
[1] Kyowa Hakko Kogyo Co Ltd, Tokyo Res Labs, Machida, Tokyo 1948533, Japan
[2] Kyowa Hakko Kogyo Co Ltd, Pharmaceut Res Inst, Nagaizumi, Shizuoka 4118731, Japan
[3] Univ Tokyo, Grad Sch Agr & Life Sci, Dept Biotechnol, Bunkyo Ku, Tokyo 1138657, Japan
关键词
D O I
10.7164/antibiotics.55.863
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Six GEX1 compounds, GEX1A/herboxidiene and its related 5 novel compounds, were isolated from a culture broth of Streptomyces sp. GEX1 compounds induced both G1 and G2/M arrest in a human normal fibroblast cell line, WI-38. All six compounds up-regulated luciferase reporter gene expression directed by enhancer/promoter of various genes, such as cdc2, IL-2 and SV40 early genes. All GEX1 compounds showed cytotoxic activities in the same order of the up-regulating activities on gene expression, suggesting that these two activities are related. Despite the up-regulating activities on the reporter gene expression, GEX1A/herboxidiene did not enhance the expression of any endogenous genes involved in the cell cycle, proliferation and apoptosis. Although the unique effects of GEX1 compounds on cell cycle and the reporter gene expression were similar to those of trichostatin A (TSA), an inhibitor of histone deacetylase (HDAC), GEX1A/herboxidiene did not affect historic acetylation in cells. In addition, GEX1A/herboxidiene treatment gave rise to the shorter sized transcripts of the cdc25A and cdc2 genes as well as the normal sized ones. These results suggest that GEX1 compounds modulate gene expression by an unknown mechanism.
引用
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页码:863 / 872
页数:10
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