New pharmacological effect of fulvestrant to prevent oxaliplatin-induced neurodegeneration and mechanical allodynia in rats.
Shota YamamotoTomohiro YamashitaMayu ItoJose M M CaaveiroNobuaki EgashiraHidetoshi Tozaki-SaitohMakoto TsudaPublished in: International journal of cancer (2018)
Oxaliplatin, which is widely used as chemotherapy for certain solid cancers, frequently causes peripheral neuropathy. Commonly described neuropathic symptoms include aberrant sensations such as mechanical allodynia (hypersensitivity to normally innocuous stimuli). Although oxaliplatin neuropathy is a dose-limiting toxicity, there are no established preventive strategies available at present. By screening several sets of small-molecule chemical libraries (more than 3,000 compounds in total) using a newly established in vitro high-throughput phenotypic assay, we identified fulvestrant, a clinically approved drug for the treatment of breast cancer in postmenopausal women, as having a protective effect on oxaliplatin-induced neuronal damage. Furthermore, histological and behavioural analyses using a rat model of oxaliplatin neuropathy demonstrated the in vivo efficacy of fulvestrant to prevent oxaliplatin-induced axonal degeneration of the sciatic nerve and mechanical allodynia. Furthermore, fulvestrant did not interfere with oxaliplatin-induced cytotoxicity against cancer cells. Thus, our findings reveal a previously unrecognised pharmacological effect of fulvestrant to prevent oxaliplatin-induced painful peripheral neuropathy without impairing its cytotoxicity against cancer cells and may represent a novel prophylactic option for patients receiving oxaliplatin chemotherapy.
Keyphrases
- high glucose
- diabetic rats
- postmenopausal women
- small molecule
- high throughput
- drug induced
- oxidative stress
- metastatic breast cancer
- squamous cell carcinoma
- emergency department
- endothelial cells
- gene expression
- physical activity
- single cell
- radiation therapy
- depressive symptoms
- spinal cord
- sleep quality
- dna methylation
- genome wide
- stress induced
- rectal cancer
- replacement therapy