Hypoxia-mediated retinal neovascularization and vascular leakage in diabetic retina is suppressed by HIF-1α destabilization by SH-1242 and SH-1280, novel hsp90 inhibitors

Abstract

In diabetic retinopathy (DR), visual deterioration is related with retinal neovascularization and vascular hyperpermeability. Anti-vascular endothelial growth factor (VEGF) agents are currently utilized to suppress retinal neovascularization and macular edema (ME); however, there are still concerns on the widespread use of them because VEGF is a trophic factor for neuronal and endothelial cells in the retina. As an alternative treatment strategy for DR, it is logical to address hypoxia-related molecules to treat DR because the retina is in relative hypoxia as DR progresses. In this study, we demonstrate that destabilization of hypoxia-inducible factor-1α (HIF-1α) by SH-1242 and SH-1280, novel heat shock protein 90 (hsp90) inhibitors, leads to suppression of hypoxia-mediated retinal neovascularization and vascular leakage in diabetic retina. In vitro experiments showed that these inhibitors inhibited hypoxia-induced upregulation of target genes of HIF-1α and further secretion of VEGF. Furthermore, these inhibitors effectively suppressed expression of target genes of HIF-1α including vegfa in the retina of oxygen-induced retinopathy (OIR) mice. Interestingly, despite hsp90 inhibition, these inhibitors do not induce definite toxicity at the level of gene expression, cellular viability, and histologic integrity. We suggest that SH-1242 and SH-1280 can be utilized in the treatment of DR, as an alternative treatment of direct VEGF inhibition. Key message: SH-1242 and SH-1280 are novel hsp90 inhibitors similar to deguelin. HIF-1α destabilization by hsp90 inhibition leads to anti-angiogenic effects. Despite hsp90 inhibition, both inhibitors do not induce definite toxicity. HIF-1α modulation can be a safer therapeutic option than direct VEGF inhibition.

Deguelin Analogue SH-1242 Inhibits Hsp90 Activity and Exerts Potent Anticancer Efficacy with Limited Neurotoxicity

“…S1). SH-1242 displayed potent inhibitory effects on HIF1a expression and viability of H1299 human NSCLC cells and on hypoxia-mediated retinal neovascularization and vascular leakage in a diabetic retina without developmental defects in zebrafish embryos (25,26). We first assessed the potency of SH-1242 against various human NSCLC cell lines.…”

“…On the basis of the potent antiangiogenic effects of deguelin and its derivatives (23,26), we further assessed the effect of SH-1242 on angiogenic activities of NSCLC cells. Because tumor angiogenesis is mediated at least in part by tumorsecreted angiogenic growth factors that interact with their surface receptors expressed on endothelial cells (33), we analyzed the effects of conditioned medium (CM) derived from H1299 cells treated with increasing concentrations of SH-1242 on the tube formation of HUVECs.…”

“…However, despite deguelin's potency, its potential Parkinsonism-like neurotoxicity may be an obstacle to further clinical development. Hence, we have synthesized a variety of deguelin analogues; of these, SH-1242, a B-and C-ring truncated analogue (25), displayed a potent antiproliferative effect against human cancer cells (25) and suppressed hypoxia-mediated retinal neovascularization and vascular leakage in diabetic retinas by suppressing hypoxia-mediated upregulation of HIF1a and VEGF expression without any obvious toxicity (26). These promising effects imply the potential of SH-1242 as a lead candidate for developing Hsp90 inhibitors.…”

Synthesis and Biological Evaluation of Novel Homoisoflavonoids for Retinal Neovascularization

“…At present there are no FDA approved small molecule drugs targeting pathological angiogenesis in the eye, although there are some promising small molecules such as squalamine, OC-10X, vatalanib, and pazopanib being developed as antiangiogenic drugs for wet AMD and PDR (www.clinicaltrials.gov). 4 To supplement these and existing drugs, novel, specific antiangiogenic small molecules need to be developed to strengthen the drug pipeline for wet AMD, PDR and ROP.…”

Aloe-emodin suppresses hypoxia-induced retinal angiogenesis via inhibition of HIF-1α/VEGF pathway

“…DR is a serious microvascular complication in the patients with diabetes mellitus, which causes vitreous hemorrhage, tractional retinal detachment and visual deterioration 8, 9. Furthermore, increased vascular permeability leads to macular edema in the patients with DR 10.…”