Pevonedistat targeted therapy inhibits canine melanoma cell growth through induction of DNA re-replication and senescence
| Autor: | Matthew A. Van Hesteren, Mike K. Huelsmeyer, Shuai Jia, Anna L F. V. Assumpção, David M. Vail, Xuan Pan, Zhanping Lu, Elizabeth A. Wood |
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| Rok vydání: | 2019 |
| Předmět: |
DNA Replication
040301 veterinary sciences DNA damage Cell Survival Cell Apoptosis Cyclopentanes 0403 veterinary science 03 medical and health sciences 0302 clinical medicine Dogs Cell Line Tumor Canine Melanoma medicine Animals Viability assay Dog Diseases Enzyme Inhibitors Melanoma General Veterinary Cell growth Chemistry 04 agricultural and veterinary sciences medicine.anatomical_structure Pyrimidines Cell culture 030220 oncology & carcinogenesis Cancer cell Cancer research Mouth Neoplasms |
| Zdroj: | Veterinary and comparative oncology. 18(3) |
| ISSN: | 1476-5829 |
| Popis: | MLN4924 (pevonedistat) is a potent and selective NEDD8-activating enzyme (NAE) inhibitor. The NEDD8-regulated neddylation system is responsible for the regulated degradation of intracellular proteins with important cellular functions in cancer cell growth, apoptosis, angiogenesis and metastasis. In human melanoma, inhibition of NAE results in induction of DNA re-replication, S phase cell cycle arrest, DNA damage and apoptosis. The study aimed to assess the anti-cancer effect of MLN4924 on canine malignant melanoma cell lines and patient samples and to elucidate the underlying mechanisms. Canine melanoma cell lines and primary patient samples were evaluated for cell viability after incubation with varying concentrations of MLN4924 or dimethyl sulfoxide. Apoptosis, cell proliferation and senescence assays were performed to address underlying mechanisms of MLN4924-mediated anti-tumour effects. Gene expression of seven previously identified deregulated genes in human melanoma was compared in sensitive vs resistant samples. MLN4924 treatment significantly reduced the viability of canine melanoma cell lines and primary samples in a dose- and time-dependent manners. MLN4924 promoted cell apoptosis and inhibited cell growth through induction of DNA re-replication and cell senescence. While the majority of canine melanoma samples demonstrated sensitivity at nanomolar ranges, some samples were resistant to the treatment. Modulation of P21 levels correlated with canine melanoma cell sensitivity. These results provided justification for further exploration of MLN4924 as a treatment of canine melanoma. |
| Databáze: | OpenAIRE |
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