title: Biochanin A inhibits endothelial cell functions and proangiogenic pathways: implications in glioma therapy.
abstract: Malignant gliomas, such as glioblastoma multiforme, are highly vascularized tumors of the central nervous system. A rich network of angiogenic vessels supporting glioma growth is an important therapeutic target in glioma therapy. In the past few years, small molecules have gained interest as multitargeting therapies for cancer. Biochanin A is a small, natural dietary isoflavone known for its anticancer potential. Previously, we have found that biochanin A inhibits invasion in human glioblastoma cells. In this study, we elucidated the antiangiogenic mechanisms of biochanin A using rat brain tumor (C6) and murine brain endothelial (bEnd.3) cells and an ex-vivo chick chorioallantoic membrane model. Biochanin A inhibited endothelial cell functions such as cell viability, migration, and invasion, as analyzed using MTT, scratch wound, and gelatin zymography assays. Activation of proangiogenic proteins (ERK/AKT/mTOR) was inhibited. Biochanin A also inhibited chemical hypoxia-inducible factor-1α and vascular endothelial growth factor in C6 cells. Results of chick chorioallantoic membrane assay showed that biochanin A inhibited blood vessel formation ex vivo. As these results suggest that biochanin A directly targets different facets of angiogenesis in vitro and ex vivo, this study provides a rationale for future preclinical evaluation of its efficacy against angiogenic gliomas.
authors.affiliation: aDepartment of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, Kentucky bDepartment of Biomedical and Pharmaceutical Sciences, Division of Health Sciences, College of Pharmacy, ISU Biomedical Research Institute, Idaho State University, Pocatello, Idaho cDepartment of Pharmaceutical Sciences, Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Jain
authors.forename: James C K
authors.initials: JC
authors.lastname: Lai
authors.forename: Alok
authors.initials: A
authors.lastname: Bhushan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D019833:Genistein / Q000494:pharmacology*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019833:Genistein; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020778:Matrix Metalloproteinase 2; C004541:biochanin A