6-(1-oxobutyl)-5,8-dimetoxy-1,4-naphthoquinone inhibits the growth of MCF-7 cells via inhibition of angiogenesis and hypoxia inducible factor alpha

Introduction

Hypoxia induces the transcription of various genes that are involved in angiogenesis and anaerobic metabolism necessary for the growth of tumor cells. Hypoxia-inducible factor (HIF)-1α regulates genes that are involved in the response to hypoxia and promotes neoangiogenesis in cancer. Thus, 6-(1-oxobutyl)-5,8-dimetoxy-1,4-naphthoquinone (OXO) was synthesized, to develop an anticancer agent with antiangiogenic activity in hypoxic cancer cells.

Method

The XTT (2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide) assay for cytotoxicity, ELISA (enzyme linked immunosorbent assay), RT-PCR and Western blotting analysis were employed in MCF-7 human breast cancer cells under hypoxic conditions.

Results

OXO exhibited cytotoxicity against MCF-7 cells, human breast cancer cells with an IC₅₀ of 20 μmol/l. OXO also reduced the levels of vascular endothelial cell growth factor (VEGF) and HIF-1α in MCF cells exposed to hypoxia. Similarly, OXO downregulated the expression of HIF-1 and VEGF by western blotting and RT-PCR. In addition, OXO inhibited the basic fibroblast growth factor (bFGF) induced proliferation, tube formation of human umbilical vein endothelial cells, and disrupted the neovasularization in bFGF treated Matrigel in vivo.

Conclusion

Taken together, OXO may exert antitumor and antiangiogenic activity against MCF-7 cells via regulation of HIF-1α and VEGF.