Pyridazinone Derivatives Limit Osteosarcoma-Cells Growth In Vitro and In Vivo

SIMPLE SUMMARY: There is a dire need for novel therapeutic interventions to treat osteosarcoma. Pyridazinone derivatives have proven some efficacy in several cancer models, but their effect on osteosarcoma is yet to be evaluated. Our goal was to synthesize and evaluate, both in vitro and in vivo, some pyridazinone derivatives to provide a proof of concept of their potential as anti-osteosarcoma molecules. We demonstrated that our newly synthesized pyridazinone scaffold-based molecules might be hit-candidates to develop new therapeutic avenues for multi-therapy purposes. ABSTRACT: Osteosarcoma is a rare primary bone cancer that mostly affects children and young adults. Current therapeutic approaches consist of combining surgery and chemotherapy but remain unfortunately insufficient to avoid relapse and metastases. Progress in terms of patient survival has remained the same for 30 years. In this study, novel pyridazinone derivatives have been evaluated as potential anti-osteosarcoma therapeutics because of their anti-type 4 phosphodiesterase activity, which modulates the survival of several other cancer cells. By using five—four human and one murine osteosarcoma—cell lines, we demonstrated differential cytotoxic effects of four pyridazinone scaffold-based compounds (mitochondrial activity and DNA quantification). Proapoptotic (annexin V positive cells and caspase-3 activity), anti-proliferative (EdU integration) and anti-migratory effects (scratch test assay) were also observed. Owing to their cytotoxic activity in in vitro conditions and their ability to limit tumor growth in a murine orthotopic osteosarcoma model, our data suggest that these pyridazinone derivatives might be hit-candidates to develop new therapeutic strategies against osteosarcoma.