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6-(1-oxobutyl)-5,8-dimethoxy-1,4-naphthoquinone exerts anti-angiogenic activity via inhibition of vascular endothelial cell growth factor and hypoxia-inducible factor 1 alpha in hypoxia-exposed MCF breast cancer cells

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Background

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

Methods

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

Results

OXO showed cytotoxicity against MCF-7 cells, human breast M. OXO also reduced the levels cancer cells with an IC50 value of 10 μ 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, inhibited tube formation of human umbilical vein endothelial cells (HUVECs) and also disrupted the neovascularization in bFGF-treated Matrigel in vivo.

Conclusion

Taken together, these results show that OXO may exert anti-tumor and anti-angiogenic activity against MCF-7 cells via regulation of HIF-1α and VEGF.

Figure 1
figure1

Cytotoxicity.

Figure 2
figure2

Effect of OXO on the proliferation of bFGF-treated HUVECs.

Figure 3
figure3

Effect of OXO on the tube formation of bFGF-treated HUVECs.

Figure 4
figure4

Effect of OXO on VEGF and HIF-1α in MCF-7 cells exposed to hypoxia.

Figure 5
figure5

Effect of OXO on the content of hemoglobin in bFGF-treated Matrigel.

References

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    Forsythe JA, Jiang BH, Lyer NV, Agani F, Leung SW, Koos RD, et al: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996, 16: 4604-4613.

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    Richard DE, Berra E, Pouyssegur J: Angiogenesis: how a tumor adapts to hypoxia. Biochem Biophys Res Commun. 1999, 266: 718-722. 10.1006/bbrc.1999.1889.

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    Ferrara H, Gerber H-P, Lecouter J: The biology of VEGF and its receptors. Nat Med. 2003, 9: 669-676. 10.1038/nm0603-669.

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Lee, H., Kim, S. 6-(1-oxobutyl)-5,8-dimethoxy-1,4-naphthoquinone exerts anti-angiogenic activity via inhibition of vascular endothelial cell growth factor and hypoxia-inducible factor 1 alpha in hypoxia-exposed MCF breast cancer cells. Breast Cancer Res 7, P4.01 (2005) doi:10.1186/bcr1131

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Keywords

  • Breast Cancer Cell
  • Fibroblast Growth Factor
  • Human Umbilical Vein Endothelial Cell
  • Human Breast Cancer Cell
  • Tube Formation