Systemic anti-vascular endothelial growth factor therapies induce a painful sensory neuropathy
| Autor: | Isabel Pintelon, Jean-Pierre Timmermans, Theo F. Meert, Joke Dhondt, Anneleen Daniels, Koen Poesen, Peter Carmeliet, Rony Nuydens, Diether Lambrechts, An Verheyen, Eve Peeraer |
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| Rok vydání: | 2012 |
| Předmět: |
Vascular Endothelial Growth Factor A
medicine.medical_specialty Indoles Paclitaxel medicine.medical_treatment Mice Transgenic Biology Vascular endothelial growth inhibitor Neuroprotection chemistry.chemical_compound Mice Polyneuropathies Internal medicine Ganglia Spinal medicine Animals Growth factor receptor inhibitor Pyrroles Protein Kinase Inhibitors Pain Measurement Neurons Behavior Animal Growth factor Antibodies Neutralizing Vascular Endothelial Growth Factor Receptor-2 Vascular endothelial growth factor B Vascular endothelial growth factor Vascular endothelial growth factor A Endocrinology Vascular endothelial growth factor C chemistry Cancer research Neuralgia Neurology (clinical) Human medicine |
| Zdroj: | Brain |
| ISSN: | 1460-2156 0006-8950 |
| Popis: | Systemic vascular endothelial growth factor inhibition, in combination with chemotherapy, improves the outcome of patients with metastatic cancer. Peripheral sensory neuropathies occurring in patients receiving both drugs are attributed to the chemotherapy. Here, we provide unprecedented evidence that vascular endothelial growth factor receptor inhibitors trigger a painful neuropathy and aggravate paclitaxel-induced neuropathies in mice. By using transgenic mice with altered neuronal vascular endothelial growth factor receptor expression, systemic inhibition of vascular endothelial growth factor receptors was shown to interfere with the endogenous neuroprotective activities of vascular endothelial growth factor on sensory neurons. In vitro , vascular endothelial growth factor prevented primary dorsal root ganglion cultures from paclitaxel-induced neuronal stress and cell death by counteracting mitochondrial membrane potential decreases and normalizing hyperacetylation of α-tubulin. In contrast, vascular endothelial growth factor receptor inhibitors exerted opposite effects. Intriguingly, vascular endothelial growth factor or vascular endothelial growth factor receptor inhibitors exerted their effects through a mechanism whereby Hdac6, through Hsp90, controls vascular endothelial growth factor receptor-2-mediated expression of the anti-apoptotic Bcl2. Our observations that systemic anti-vascular endothelial growth factor therapies interfere with the neuroprotective activities of vascular endothelial growth factor may have important implications for the application of anti-vascular endothelial growth factor therapies in cancer patients. * Abbreviations : VEGF : vascular endothelial growth factor |
| Databáze: | OpenAIRE |
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