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Mridul Mukherji, Divya Teja Vavilala, Prakash Swami, VK Chaithanya Ponnaluri; Treatment of retinal capillary hemangioblastoma using inhibitors of the HIF pathway. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4643. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal capillary hemangioblastoma (RCH, aka blood vessel tumor) is observed in patients with mutations in the VHL tumor suppressor gene. This disease is a multisystem tumor syndrome where the mutated VHL protein (pVHL) does not bind and degrade the regulatory α-subunits of the hypoxia-inducible factor even under normoxic conditions. This results in overexpression of HIF-dependent pro-angiogenic factors. As a result, hemangioblastomas of retina, CNS, and kidney are highly vascular in nature. All current therapies for RCH have significant limitations and side-effects; e.g., photocoagulation and cryotherapies cause tissue destruction and inflammation, while anti-VEGF therapies had minimal detectable beneficial effects. This lack of efficacy of anti-VEGF therapies is possibly due to overexpression of other pro-angiogenic factors (e.g. EPO, PDGF, etc.) in RCH. Thus, there remains a critical need for the development of an effective agent for the treatment of RCH. Since inhibition of the HIF pathway is sufficient to suppress tumor growth by mutated VHL cells in mouse xenografts, it offers an attractive target to treat RCH.
Four renal cell carcinoma derived cell lines (RCC4, T314, PRC3 and WT8) and two human retinal pigment epithelial cells (D407 and ARPE19) were used to evaluate the expression of cancer stem cell (CSM) and angiogenic markers. Honokiol, digoxin and doxorubicin were used as HIF inhibitors in cell culture model. Inhibition of CSM and angiogenic marker expression by these small molecules was evaluated using qPCR, western blot analysis and ELISA.
RCC4 and PRC3 cells which lack VHL showed upregulation of HIF pathway, thus induction of CSM and pro-angiogenic genes as compared to T314 and WT8 (both have functional pVHL), respectively. In D407 and ARPE19 cells HIF is stabilized under hypoxic conditions, thereby mimicking VHL disease phenotype, showing induction of CSM and pro-angiogenic genes. Honokiol, digoxin and doxorubicin significantly inhibited the HIF pathway, thus lowering the induction of CSM and pro-angiogenic genes in these cell lines.
Loss of VHL in RCH leads to activation of HIF pathway and thus induces expression of CSM and pro-angiogenic genes. Small molecule inhibitors of HIF pathway like honokiol, digoxin and doxorubicin lowered expression of CSM and pro-angiogenic genes, and thus presents a novel therapeutic strategy for RCH treatment.
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