title: Honokiol inhibits HIF pathway and hypoxia-induced expression of histone lysine demethylases.
abstract: Hypoxia-inducible-factor (HIF)-mediated expression of pro-angiogenic genes under hypoxic conditions is the fundamental cause of pathological neovascularization in retinal ischemic diseases and cancers. Recent studies have shown that histone lysine demethylases (KDMs) play a key role in the amplification of HIF signaling and expression of pro-angiogenic genes. Thus, the inhibitors of the HIF pathway or KDMs can have profound therapeutic value for diseases caused by pathological neovascularization. Here, we show that hypoxia-mediated expression of KDMs is a conserved process across multiple cell lines. Moreover, we report that honokiol, a biphenolic phytochemical extracted from Magnolia genus which has been used for thousands of years in the traditional Japanese and Chinese medicine, is a potent inhibitor of the HIF pathway as well as hypoxia-induced expression of KDMs in a number of cancer and retinal pigment epithelial cell lines. Further, treating the cells with honokiol leads to inhibition of KDM-mediated induction of pro-angiogenic genes (adrenomedullin and growth differentiation factor 15) under hypoxic conditions. Our results provide an evidence-based scientific explanation for therapeutic benefits observed with honokiol and warrant its further clinical evaluation for the treatment of pathological neovascularization in retinal ischemic diseases and cancers.
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, MO 64108-2718, USA.
authors.forename: Divya Teja
authors.initials: DT
authors.lastname: Vavilala
authors.forename: V K Chaithanya
authors.initials: VK
authors.lastname: Ponnaluri
authors.forename: Ramya Krishna
authors.initials: RK
authors.lastname: Vadlapatla
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Pal
authors.forename: Ashim K
authors.initials: AK
authors.lastname: Mitra
authors.forename: Mridul
authors.initials: M
authors.lastname: Mukherji
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors*; D017705:Lignans / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D020533:Angiogenesis Inhibitors; D001713:Biphenyl Compounds; D056466:Histone Demethylases; D051793:Hypoxia-Inducible Factor 1; D017705:Lignans; D010100:Oxygen; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols