期刊
JOURNAL OF NATURAL PRODUCTS
卷 72, 期 12, 页码 2104-2109出版社
AMER CHEMICAL SOC
DOI: 10.1021/np9005794
关键词
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资金
- NIH/NCI [CA98787]
- NOAA/NIUST [NA 16RU1496]
- NIH/NCRR [P20RR021929]
- NIH [C06 RR-14503-01]
The transcription factor hypoxia-inducible factor-1 (HIF-1) represents an important molecular target for anticancer drug discovery. In a T47D cell-based reporter assay, the Caulerpa spp. algal pigment caulerpin (1) inhibited hypoxia-induced as well as 1,10-phenanthroline-induced HIF-1 activation. The angiogenic factor vascular endothelial growth factor (VEGF) is regulated by HIF-1. Caulerpin (10 mu M) suppressed hypoxic induction of secreted VEGF protein and the ability of hypoxic T47D cell-conditioned media to promote tumor angiogenesis in vitro. Under hypoxic conditions, 1 (10 mu M) blocked the induction of HIF-1 alpha protein, the oxygen-regulated subunit that controls HIF-1 activity. Reactive oxygen species produced by mitochondrial complex III are believed to act as a signal of cellular hypoxia that leads to HIF-1 alpha protein induction and activation. Further mechanistic studies revealed that I inhibits mitochondrial respiration at electron transport chain (ETC) complex I (NADH-ubiquinone oxidoreductase). Under hypoxic conditions, it is proposed that 1 may disrupt mitochondrial ROS-regulated HIF-1 activation and HIF-1 downstream target gene expression by inhibiting the transport or delivery of electrons to complex III.
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