The histone deacetylase inhibitor valproic acid sensitizes human and canine osteosarcoma to doxorubicin

Abstract

Osteosarcoma (OS) remains an incurable and ultimately fatal disease in many patients, and novel forms of therapy are needed. Improved models of OS that more closely mimic human disease would provide more robust information regarding the utility of novel therapies. Spontaneous OS in dogs may provide such a model. Pharmacologic inhibition of histone deacetylase (HDAC) enzymes has a variety of anti-tumor effects but may demonstrate the most utility when utilized in combination with standard cytotoxic therapies. We sought to determine the in vitro and in vivo effects of the HDAC inhibitor valproic acid (VPA) on doxorubicin (DOX) sensitivity in canine and human OS. We evaluated the in vitro anti-proliferative and apoptotic effects of VPA/DOX combination treatment, alterations in histone acetylation and nuclear DOX accumulation resulting from VPA treatment, and the in vivo efficacy of combination therapy in a xenograft model. Treatment of canine and human OS cell lines with clinically achievable VPA concentrations resulted in increased histone acetylation but modest anti-proliferative effects. Pre-incubation with VPA followed by doxorubicin (DOX) resulted in significant growth inhibition and potentiation of apoptosis, associated with a dose-dependent increase in nuclear DOX accumulation. The combination of VPA and DOX was superior to either monotherapy in a canine OS xenograft model. These results demonstrate a rationale for the addition of HDAC inhibitors to current protocols for the treatment of OS and illustrate the similarities in response to HDAC inhibitors between human and canine OS, lending further credibility to the canine OS model.