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

Abstract

Purpose-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. NIH Public AccessAuthor Manuscript Cancer Chemother Pharmacol. Author manuscript; available in PMC 2012 January 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMethods-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.Results-Treatment of canine and human OS cell lines with clinically achievable VPA concentrations resulted in increased histone acetylation but modest anti-proliferative effects. Preincubation 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.Conclusion-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.

Histone deacetylase inhibitor valproic acid sensitizes B16F10 melanoma cells to cucurbitacin B treatment

“…The antitumor effect of VPA by induction of cell apoptosis has been reported in various cancers, such as small cell lung cancer, chronic lymphocytic leukemia, and hepatoma [17,34,35]. VPA treatment also sensitizes tumor cells to some first-line antitumor drugs, such as doxorubicin, cisplatin, and etoposide [16,17]. Consistent with these reports, our results demonstrated that a combination of CuB with VPA overcame the resistant compensatory response and multiploidization effect induced by CuB.…”

Valproic acid synergistically enhances the cytotoxicity of gossypol in DU145 prostate cancer cells: An iTRTAQ-based quantitative proteomic analysis

“…The effects of H3 acetylation on transcription of a host of prosurvival and transforming genes makes co-therapy using HDAC inhibitors a promising co-therapy in treatment of drug-refractory tumors to circumvent activation of survival pathways [22,34,35]. Our results demonstrate that therapeutic levels of VPA in an in vitro prostate cancer system had greatly increased the histone H3 acetylation in DU145 cells.…”

Inhibition of Enveloped Virus Infection of Cultured Cells by Valproic Acid

“…Inhibition of histone deacetylases is one of the effects of VPA on cells (54,57), which has been proposed to have an antiviral effect on latent infections (11,29,31,61). To address the implication of this mechanism on the inhibition observed in this study, the effect of TSA-another HDAC inhibitor (8)-on the infection of FMDV, SFV, SINV, VSV, VACV, LCMV, ASFV, WNV, and USUV was tested.…”

“…The proposed cellular targets of VPA are diverse, including (i) interruption of ␥-amino butyric acid (GABA) signaling, (ii) inhibition of histone deacetylases (HDAC), (iii) modulation of sodium channel activity, (iv) inhibition of glycogen synthase kinase 3, and (v) disruption of membrane lipid metabolism, including that of phosphatidylinositol (48,53,54,57,59).…”