Pre-clinical evaluation of proteasome inhibitors for canine and human osteosarcoma

摘要: Osteosarcoma, a common malignancy in large dog breeds, typically metastasises from long bones to lungs and is usually fatal within 1 2 years of diagnosis. Better therapies are needed for canine patients their human counterparts, third whom die 5 We compared the vitro sensitivity osteosarcoma cells derived 4 tumours currently used chemotherapy drugs doxorubicin carboplatin, new anti-cancer drugs. Agents targeting histone deacetylases or PARP were ineffective. Two cell lines somewhat sensitive BH3-mimetic navitoclax. The proteasome inhibitor bortezomib potently induced caspase-dependent apoptosis, at concentrations substantially lower than levels detected treated rodents. Co-treatment with either carboplatin was more toxic each agent alone. Newer inhibitors carfilzomib, ixazomib, oprozomib delanzomib manifested similar activities bortezomib. Human as cells, but slightly less newer osteoblasts inhibition physiologically relevant toxic. Such toxicity, if replicated vivo, may impair bone growth strength adolescent patients, be tolerated by which diagnosed later life. Proteasome such useful treating osteosarcoma, ultimately improve outcomes survive exposure osteoblast toxicity can managed.