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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/14308

Title: Systemic anti-vascular endothelial growth factor therapies induce a painful sensory neuropathy
Authors: Verheyen, An
PEERAER, Eve
Nuydens, Rony
Dhondt, Joke
Poesen, Koen
Pintelon, Isabel
Daniels, Anneleen
Timmermans, Jean-Pierre
MEERT, Theo
Carmeliet, Peter
Lambrechts, Diether
Issue Date: 2012
Publisher: OXFORD UNIV PRESS
Citation: BRAIN, 135, p. 2629-2641
Abstract: 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 a-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.
Notes: [Verheyen, An; Dhondt, Joke; Poesen, Koen; Lambrechts, Diether] Univ Louvain, Dept Oncol, Lab Translat Genet, B-3000 Louvain, Belgium. [Verheyen, An; Dhondt, Joke; Poesen, Koen; Carmeliet, Peter; Lambrechts, Diether] VIB, Vesalius Res Ctr, B-3000 Louvain, Belgium. [Verheyen, An; Peeraer, Eve; Nuydens, Rony; Daniels, Anneleen; Meert, Theo] Janssen Res & Dev, Dept Neurosci, B-2340 Beerse, Belgium. [Peeraer, Eve] Univ Hasselt, Biomed Res Inst, B-3590 Diepenbeek, Belgium. [Pintelon, Isabel; Timmermans, Jean-Pierre] Univ Antwerp, Lab Cell Biol & Histol, Dept Vet Sci, B-2020 Antwerp, Belgium. [Carmeliet, Peter] Univ Louvain, Lab Angiogenesis & Neurovasc Link, B-3000 Louvain, Belgium. diether.lambrechts@vib-kuleuven.be
URI: http://hdl.handle.net/1942/14308
DOI: 10.1093/brain/aws145
ISI #: 000308873600007
ISSN: 0006-8950
Category: A1
Type: Journal Contribution
Validation: ecoom, 2013
Appears in Collections: Research publications

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