ARQ-197, a small-molecule inhibitor of c-Met, reduces tumour burden and prevents myeloma-induced bone disease in vivo.

Autor: Lath DL; Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom.; Mellanby Centre for Bone Research, Medical School, University of Sheffield, Sheffield, United Kingdom., Buckle CH; Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom.; Mellanby Centre for Bone Research, Medical School, University of Sheffield, Sheffield, United Kingdom., Evans HR; Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom.; Mellanby Centre for Bone Research, Medical School, University of Sheffield, Sheffield, United Kingdom., Fisher M; Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom., Down JM; Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom.; Mellanby Centre for Bone Research, Medical School, University of Sheffield, Sheffield, United Kingdom., Lawson MA; Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom.; Mellanby Centre for Bone Research, Medical School, University of Sheffield, Sheffield, United Kingdom., Chantry AD; Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom.; Mellanby Centre for Bone Research, Medical School, University of Sheffield, Sheffield, United Kingdom.; Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, United Kingdom.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2018 Jun 20; Vol. 13 (6), pp. e0199517. Date of Electronic Publication: 2018 Jun 20 (Print Publication: 2018).
DOI: 10.1371/journal.pone.0199517
Abstrakt: The receptor tyrosine kinase c-Met, its ligand HGF, and components of the downstream signalling pathway, have all been implicated in the pathogenesis of myeloma, both as modulators of plasma cell proliferation and as agents driving osteoclast differentiation and osteoblast inhibition thus, all these contribute substantially to the bone destruction typically caused by myeloma. Patients with elevated levels of HGF have a poor prognosis, therefore, targeting these entities in such patients may be of substantial benefit. We hypothesized that ARQ-197 (Tivantinib), a small molecule c-Met inhibitor, would reduce myeloma cell growth and prevent myeloma-associated bone disease in a murine model. In vitro we assessed the effects of ARQ-197 on myeloma cell proliferation, cytotoxicity and c-Met protein expression in human myeloma cell lines. In vivo we injected NOD/SCID-γ mice with PBS (non-tumour bearing) or JJN3 cells and treated them with either ARQ-197 or vehicle. In vitro exposure of JJN3, U266 or NCI-H929 cells to ARQ-197 resulted in a significant inhibition of cell proliferation and an induction of cell death by necrosis, probably caused by significantly reduced levels of phosphorylated c-Met. In vivo ARQ-197 treatment of JJN3 tumour-bearing mice resulted in a significant reduction in tumour burden, tumour cell proliferation, bone lesion number, trabecular bone loss and prevented significant decreases in the bone formation rate on the cortico-endosteal bone surface compared to the vehicle group. However, no significant differences on bone parameters were observed in non-tumour mice treated with ARQ-197 compared to vehicle, implying that in tumour-bearing mice the effects of ARQ-197 on bone cells was indirect. In summary, these res ults suggest that ARQ-197 could be a promising therapeutic in myeloma patients, leading to both a reduction in tumour burden and an inhibition of myeloma-induced bone disease.
Competing Interests: The authors have declared no competing interests exist.
Databáze: MEDLINE
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