Research
VHL hemangioblastomas show HIF-1α signal concentrated in the nuclei. After propranolol or ICI treatment of cells, HIF-1α signal is less accumulated in the nuclei and rather dispersed over the cytoplasm. This effect is not observed with atenolol, a specific β1 blocker, with a concentration of HIF-1 α in nuclei as in untreated hemangioblastoma cells (control). [Adapted from (2019) Sci Rep. Jul 11;9(1):10062]
29 Jul 2019
Identified a promising drug for von Hippel Lindau disease treatment
A study recently published in Scientific Reports and lead by Dr. Luisa Botella, belonging to the Molecular Biomedicine of Centro de Investigaciones Biológicas (CSIC), identifies a compound postulated as a good drug to treat von Hippel-Lindau disease (VHL), a rare genetic disorder associated with cancer predisposition.
The compound which has been characterized is named ICI118,551 and it is a specific β2 adrenergic blocker. In this work it is shown that this compound has the same antiangiogenic and pro-apoptotic properties as propranolol, a non-specific adrenergic β-blocker which binds both β1 and β2 receptors. The same research group demonstrated that propranolol slows tumoral progression of hemangioblastomas in VHL patients, delaying repetition surgeries, and got its designation as orfan drug for this disease. Propanolol due to its binding to β1 adrenergic receptors leads to hypotension and bradichardia, side effects dangerous for hypotense patients. Now, in addition to the demonstration that antiangiogenic and proapoptotic effects of both propranolol and ICI118,551 are due to the β2 blockade, ICI118,551, being specific of these receptors, is proposed as the election drug in the von Hippel Lindau disease.
The article published in Sci Rep. presents the molecular action basis of ICI118,551 as a β2 specific blocker, probing that it is partially hampering the hypoxia inducible factor (HIF) constitutive signaling operating in VHL hemangioblastomas. This molecular mechanism is collected in a patent for repurposing ICI118,551 in VHL treatment recently licenced to CyclePharma (Cambridge UK), a pharma company specialized in orphan drug development for rare diseases.
This study is the result of a translational collaborative research with the Spanish Alliance of families for the von Hippel Lindau disease (VHL) and Dr. Daniel Aguirre, from the Jiménez Díaz Foundation Hospital, reference VHL neurosurgeon.
Reference: “The β2-adrenergic receptor antagonist ICI-118,551 blocks the constitutively activated HIF signalling in hemangioblastomas from von Hippel-Lindau disease”. Cuesta AM, Albiñana V, Gallardo-Vara E, Recio-Poveda L, de Rojas-P I, de Las Heras KVG, Aguirre DT, Botella LM (2019) Sci Rep. Jul 11;9(1):10062. doi: 10.1038/s41598-019-46448-6