Evaluation of anti-HIF and anti-angiogenic properties of honokiol for the treatment of ocular neovascular diseases.

Pathological activation of the hypoxia-inducible-factor (HIF) pathway leading to expression of pro-angiogenic genes, such as vascular endothelial growth factor (VEGF), is the fundamental cause of neovascularization in ocular ischemic diseases and cancers. We have shown that pure honokiol inhibits the HIF pathway and hypoxia-mediated expression of pro-angiogenic genes in a number of cancer and retinal pigment epithelial (RPE) cell lines. The crude extracts, containing honokiol, from Magnolia plants have been used for thousands of years in the traditional oriental medicine for a number of health benefits. We have recently demonstrated that daily intraperitoneal injection of honokiol starting at postnatal day (P) 12 in an oxygen induced retinopathy mouse model significantly reduced retinal neovascularization at P17. Here, we evaluate the mechanism of HIF inhibition by honokiol in RPE cells. Using chromatin immunoprecipitation experiments, we demonstrate that honokiol inhibits binding of HIF to hypoxia-response elements present on VEGF promoter. We further show using a number of in vitro angiogenesis assays that, in addition to anti-HIF effect, honokiol manifests potent anti-angiogenic effect on human retinal micro vascular endothelial cells. Our results suggest that honokiol possesses potent anti-HIF and anti-angiogenic properties. These properties of honokiol make it an ideal therapeutic agent for the treatment of ocular neovascular diseases and solid tumors.

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.

The chemical biology of branched-chain lipid metabolism.

Mammalian metabolism of some lipids including 3-methyl and 2-methyl branched-chain fatty acids occurs within peroxisomes. Such lipids, including phytanic and pristanic acids, are commonly found within the human diet and may be derived from chlorophyll in plant extracts. Due to the presence of a methyl group at its beta-carbon, the well-characterised beta-oxidation pathway cannot degrade phytanic acid. Instead its alpha-methylene group is oxidatively excised to give pristanic acid, which can be metabolised by the beta-oxidation pathway. Many defects in the alpha-oxidation pathway result in an accumulation of phytanic acid, leading to neurological distress, deterioration of vision, deafness, loss of coordination and eventual death. Details of the alpha-oxidation pathway have only recently been elucidated, and considerable progress has been made in understanding the detailed enzymology of one of the oxidative steps within this pathway. This review summarises these recent advances and considers the roles and likely mechanisms of the enzymes within the alpha-oxidation pathway.