11,11'-dideoxy-verticillin, a compound of the novel epidithiodioxopiprazine structural class, is isolated from the traditional Chinese medicinal herb Shiraia bambusicola. The present study demonstrated for the first time that 11,11'-dideoxy-verticillin has potent
tyrosine kinase-inhibitory and anti-
tumor activities. In the cell-free ELISA
tyrosine kinase assay, 11,11'-dideoxy-verticillin significantly inhibited the activities of
epidermal growth factor receptor (EGFR),
vascular endothelial growth factor receptor-1/fms-like
tyrosine kinase-1 (VEGFR-1/Flt-1) and human
epidermal growth factor receptor-2 (HER2/ErbB-2), with relative specificity on EGFR and
VEGFR-1 with IC50s of 0.136+/-0.109 and 1.645+/-0.885 nM, respectively. Exposure of 11,11'-dideoxy-verticillin for 1 h to EGFR-overexpressed MDA-MB-468 human
breast carcinoma cells and HER2-overexpressed SK-OV-3 human ovarian
adenocarcinoma cells resulted in obvious inhibition of
EGF-induced phosphorylation of EGFR and HER2. In addition, 11,11'-dideoxy-verticillin also inhibited the
EGF-induced phosphorylation of Erk1/2, but had no effect on the phosphorylation of AKT in both tumor cell lines. Moreover, 11,11'-dideoxy-verticillin has potent anti-
tumor activity. In vitro cytotoxicity assay showed that 11,11'-dideoxy-verticillin potently inhibited the proliferation of four human
breast tumor cell lines with an average IC50 value of 0.2 microM. In vivo, 11,11'-dideoxy-verticillin exhibited remarkable efficacy against mice
sarcoma 180 and
hepatoma 22 after daily i.p. administration of 0.5 or 0.75 mg/kg with inhibition rates ranging from 45.0 to 72.4%. Treated with 11,11'-dideoxy-verticillin at 0.5-2.0 microM for 36 h, MB-MB-468 cells exhibited significant apoptotic morphological changes. At low concentrations (0.0625-0.5 microM) for 24 h, 11,11'-dideoxy-verticillin induced a dose-dependent accumulation of MDA-MB-468 cells in the G2/M phase of the cell cycle. These results indicate that 11,11'-dideoxy-verticillin is a naturally derived
growth factor receptor tyrosine kinase inhibitor with potent anti-
tumor activity.