Novel lysyl oxidase inhibitors attenuate hallmarks of primary myelofibrosis in mice
| Autor: | Orly Leiva, Alison D. Findlay, Shinobu Matsuura, Vipul C. Chitalia, Hector A. Lucero, Seng Kah Ng, Wolfgang Jarolimek, Katya Ravid, Craig Ivan Turner |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
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 |
| Zdroj: | Int J Hematol |
| ISSN: | 1865-3774 0925-5710 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink