Hisanori Hattori a, Kensuke Okuda a, Tetsuji Murase a, Yuki Shigetsura a, Kosuke Narise a, Gregg L. Semenza b,c,d,e,f,g,h, Hideko Nagasawa a,⇑
Institutions
a Laboratory of Medicinal & Pharmaceutical Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan b Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
c Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
d Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
e Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
f Department of Radiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
g Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
h McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Abstract
The tumor microenvironment is characterized by hypoxia, low-nutrient levels, and acidosis. A natural product chemistry-based approach was used to discover small molecules that modulate adaptive responses to a hypoxic microenvironment through the hypoxia-inducible factor (HIF)-1 signaling path- ways. Five compounds, such as baccharin (3), beturetol (4), kaempferide (5), isosakuranetin (6), and drup- anin (9), that modulate HIF-1-dependent luciferase activity were identified from Brazilian green propolis using reporter assay. Compounds 3, 9 and 5 reduced HIF-1-dependent luciferase activity. The cinnamic acid derivatives 3 and 9 significantly inhibited expression of the HIF-1a protein and HIF-1 downstream target genes such as glucose transporter 1, hexokinase 2, and vascular endothelial growth factor A. They also exhibited significant anti-angiogenic effects in the chick chorioallantoic membrane (CAM) assay at doses of 300 ng/CAM. On the other hand, flavonoids 4 and 6 induced HIF-1-dependent luciferase activity and expression of HIF-1 target genes under hypoxia. The contents (g/100 g extract) of the HIF-1-modu- lating compounds in whole propolis ethanol extracts were also determined based on liquid chromatog- raphy–electrospray ionization mass spectrometry as 1.6 (3), 14.2 (4), 4.0 (5), 0.7 (6), and 0.7 (9), respectively. These small molecules screened from Brazilian green propolis may be useful as lead compounds for the development of novel therapies against ischemic cardiovascular disease and cancer based on their ability to induce or inhibit HIF-1 activity, respectively.
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