Honokiol inhibits pathological retinal neovascularization in oxygen-induced retinopathy mouse model.
Aberrant activation of the hypoxia inducible factor (HIF) pathway is the underlying cause of retinal neovascularization, one of the most common causes of blindness worldwide. The HIF pathway also plays critical roles during tumor angiogenesis and cancer stem cell transformation. We have recently shown that honokiol is a potent inhibitor of the HIF pathway in a number of cancer and retinal pigment epithelial cell lines. Here we evaluate the safety and efficacy of honokiol, digoxin, and doxorubicin, three recently identified HIF inhibitors from natural sources. Our studies show that honokiol has a better safety to efficacy profile as a HIF inhibitor than digoxin and doxorubicin. Further, we show for the first time that daily intraperitoneal injection of honokiol starting at postnatal day (P) 12 in an oxygen-induced retinopathy (OIR) mouse model significantly reduced retinal neovascularization at P17. Administration of honokiol also prevents the oxygen-induced central retinal vaso-obliteration, characteristic feature of the OIR model. Additionally, honokiol enhanced physiological revascularization of the retinal vascular plexuses. Since honokiol suppresses multiple pathways activated by HIF, in addition to the VEGF signaling, it may provide advantages over current treatments utilizing specific VEGF antagonists for ocular neovascular diseases and cancers.
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, MO 64108-2718, USA.
Divya Teja
DT
Vavilala
Bliss E
BE
O'Bryhim
V K Chaithanya
VK
Ponnaluri
R Sid
RS
White
Jeff
J
Radel
R C Andrew
RC
Symons
Mridul
M
Mukherji
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D002460:Cell Line; D004077:Digoxin / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017705:Lignans / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D015861:Retinal Neovascularization / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D015533:Transcriptional Activation / Q000187:drug effects; D000498:Allyl Compounds; D010636:Phenols
D000903:Antibiotics, Antineoplastic; D001713:Biphenyl Compounds; D004077:Digoxin; D004317:Doxorubicin; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D051793:Hypoxia-Inducible Factor 1; D017705:Lignans; D010100:Oxygen; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols
Angiogenesis; HIF; HRE; Honokiol; Hypoxia signaling; IP; OIR; OIR-model; P; PHD; Retinopathy; Transcription regulation; VEGF; VHL; hypoxia inducible factor; hypoxia response element; intraperitoneal; oxygen-induced retinopathy; postnatal day; prolyl hydroxylation domain; vascular endothelial growth factor; von Hippel–Lindau