Acta Pharmacologica Sinica (2009) 30: 605-616; doi: 10.1038/aps.2009.8; published online 6th April 2009

Aim: To investigate the effects of dauricine (Dau) on insulin-like growth factor-I (IGF-I)-induced hypoxia inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression in human breast cancer cells (MCF-7). 

Methods: Serum-starved MCF-7 cells were pretreated for 1 h with different concentrations of Dau, followed by incubation with IGF-I for 6 h.  HIF-1α and VEGF protein expression levels were analyzed by Western blotting and ELISA, respectively.  HIF-1α and VEGF mRNA levels were determined by real-time PCR.  In vitro angiogenesis was observed via the human umbilical vein endothelial cell (HUVEC) tube formation assay.  An in vitro invasion assay on HUVECs was performed. 

Results: Dau significantly inhibited IGF-I-induced HIF-1α protein expression but had no effect on HIF-1α mRNA expression. However, Dau remarkably suppressed VEGF expression at both protein and mRNA levels in response to IGF-I. Mechanistically, Dau suppressed IGF-I-induced HIF-1α and VEGF protein expression mainly by blocking the activation of PI-3K/AKT/mTOR signaling pathway. In addition, Dau reduced IGF-I-induced HIF-1α protein accumulation by inhibiting its synthesis as well as by promoting its degradation. Functionally, Dau inhibited angiogenesis in vitro. Moreover, Dau had a direct effect on IGF-I-induced invasion of HUVECs.

Conclusion: Dau inhibits human breast cancer angiogenesis by suppressing HIF-1α protein accumulation and VEGF expression, which may provide a novel potential mechanism for the anticancer activities of Dau in human breast cancer. 

Keywords: dauricine; angiogenesis; insulin-like growth factor-I; hypoxia inducible factor 1α; vascular endothelial growth factor

^# Now in Department of Biochemistry and Molecular Biology, Guangdong Medical College , Zhanjiang 524023, China.