Systemic anti-vascular endothelial growth factor therapies induce a painful sensory neuropathy.
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.
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, B-3000 Leuven, Belgium.
An
A
Verheyen
Eve
E
Peeraer
Rony
R
Nuydens
Joke
J
Dhondt
Koen
K
Poesen
Isabel
I
Pintelon
Anneleen
A
Daniels
Jean-Pierre
JP
Timmermans
Theo
T
Meert
Peter
P
Carmeliet
Diether
D
Lambrechts
D000818:Animals; D057134:Antibodies, Neutralizing / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009437:Neuralgia / Q000139:chemically induced* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D010147:Pain Measurement; D011115:Polyneuropathies / Q000139:chemically induced* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000633:toxicity*; D011758:Pyrroles / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D057134:Antibodies, Neutralizing; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C116890:Semaxinib; D040301:Vascular Endothelial Growth Factor Receptor-2; D017239:Paclitaxel