The 5-lipoxygenase inhibitor tepoxalin induces oxidative damage and altered PTEN status prior to apoptosis in canine osteosarcoma cell lines
| Autor: | Jennifer J. Bushey, Corri B. Levine, Carolyn S. Sevier, D. Cavatorta, John P. Loftus, Joseph J. Wakshlag |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
chemistry.chemical_classification
Reactive oxygen species General Veterinary biology 040301 veterinary sciences 04 agricultural and veterinary sciences 0403 veterinary science 03 medical and health sciences 0302 clinical medicine chemistry Tepoxalin Apoptosis Annexin 030220 oncology & carcinogenesis biology.protein medicine Cancer research PTEN Tensin Kinase activity Protein kinase B medicine.drug |
| Zdroj: | Veterinary and Comparative Oncology. 14:e17-e30 |
| ISSN: | 1476-5810 |
| DOI: | 10.1111/vco.12094 |
| Popis: | The 5-lipoxygenase (5-LOX) inhibitor tepoxalin has been shown to slow canine osteosarcoma (OSA) tumour xenografts growth, yet the mechanisms are poorly elucidated. Further examination of tepoxalin in canine OSA cell lines shows that tepoxalin treated cells undergo apoptosis through caspase-3 activation and annexin staining. Interestingly, apoptosis is superseded by an increase in reactive oxygen species (ROS), as measured by activation of dihydrorhodamine 123 and mitosox. This increase in ROS appears to be related to the 5-LOX inhibitor regardless of cellular 5-LOX status, and was not observed after treatment with the tepoxalin metabolite RWJ20142. Additionally, 5-LOX inhibition by tepoxalin appears to increase phosphatase and tensin (PTEN) homolog activity by preventing its alkylation or oxidation. PTEN modification or inhibition allows phosphoinositide-3 (PI3) kinase activity thereby heightening activation of protein kinase B (AKT) phosphorylation. Our data suggest that off target oxidation and LOX inhibition play roles in the apoptotic response. |
| Databáze: | OpenAIRE |
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