Novel lysyl oxidase inhibitors attenuate hallmarks of primary myelofibrosis in mice
| العنوان: | Novel lysyl oxidase inhibitors attenuate hallmarks of primary myelofibrosis in mice |
|---|---|
| المؤلفون: | Orly Leiva, Alison D. Findlay, Shinobu Matsuura, Vipul C. Chitalia, Hector A. Lucero, Seng Kah Ng, Wolfgang Jarolimek, Katya Ravid, Craig Ivan Turner |
| المصدر: | Int J Hematol |
| بيانات النشر: | Springer Science and Business Media LLC, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, Ruxolitinib, Biological Availability, Lysyl oxidase, Pharmacology, Article, Protein-Lysine 6-Oxidase, Mice, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Megakaryocyte, Fibrosis, Animals, Medicine, Enzyme Inhibitors, Myelofibrosis, Myeloproliferative neoplasm, business.industry, Hematology, medicine.disease, Transplantation, Disease Models, Animal, Treatment Outcome, medicine.anatomical_structure, Primary Myelofibrosis, 030220 oncology & carcinogenesis, Female, Bone marrow, Bone Marrow Neoplasms, business, 030215 immunology, medicine.drug |
| الوصف: | Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm (MPN) that usually portends a poor prognosis with limited therapeutic options available. Currently only allogeneic stem cell transplantation is curative in those who are candidates, while administration of the JAK1/2 inhibitor ruxolitonib carries a risk of worsening cytopenia. The limited therapeutic options available highlight the need for the development of novel treatments for PMF. Lysyl oxidase (LOX), an enzyme vital for collagen cross-linking and extracellular matrix stiffening, has been found to be up-regulated in PMF. Herein, we evaluate two novel LOX inhibitors, PXS-LOX_1 and PXS-LOX_2, in two animal models of PMF (GATA1low and JAK2V617F-mutated mice). Specifically, PXS-LOX_1 or vehicle was given to 15-16-week-old GATA1low mice via intraperitoneal injection at a dose of 15 mg/kg four times a week for nine weeks. PXS-LOX_1 was found to significantly decrease the bone marrow fibrotic burden and megakaryocyte number compared to vehicle in both male and female GATA1low mice. Given these results, PXS-LOX_1 was then tested in 15-17-week-old JAK2V617F-mutated mice at a dose of 30 mg/kg four times a week for eight weeks. Again, we observed a significant decrease in bone marrow fibrotic burden. PXS-LOX_2, a LOX inhibitor with improved oral bioavailability, was next evaluated in 15 to 17-week-old JAK2V617F-mutated mice at a dose of 5 mg/kg p.o. four times a week for eight weeks. This inhibitor also resulted in a significant decrease in bone marrow fibrosis, albeit with a more pronounced amelioration in female mice. Taking these results together, PXS-LOX_1 and PXS-LOX_2 appear to be promising new candidates for the treatment of fibrosis in PMF. |
| تدمد: | 1865-3774 0925-5710 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6106c3bc6f8f56a4e1b8a78e82cca5a0 https://doi.org/10.1007/s12185-019-02751-6 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....6106c3bc6f8f56a4e1b8a78e82cca5a0 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 18653774 09255710 |
|---|