Effect of depsipeptide (NSC 630176), a histone deacetylase inhibitor, on human synovial sarcoma in vitro

Abstract

9039 Background: Synovial sarcoma is the fourth most common malignant soft tissue tumor of young adults. Its characteristic t(X;18)(p11.2;q11.2) leads to the production of an SYT-SSX fusion protein. Gene expression profiling studies and postulated functions of SYT-SSX both suggest altered chromatin structure is a central change in synovial sarcoma. Because chromatin structure is dependent on histone acetylation and deacetylation, the effects of depsipeptide (NSC 630176), a clinically applicable histone deacetylase inhibitor, was examined in vitro on human synovial sarcoma cell lines grown as monolayers and spheroids. Methods: Cytotoxic effects of depsipeptide (1, 10, 100, 1000 ng/ml) on SYO-1 and Fuji synovial sarcoma cells were measured by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay; results were compared against normal fibroblasts and various cancer cell lines. Apoptotic analyses by flow cytometry were subsequently performed for both monolayer and 3-dimensional synovial sarcoma cell culture systems. Results: Dramatic, dose-dependent cell death induced by depsipeptide was observed in both SYO-1 and Fuji cells at concentrations as low as 1 ng/ml, within 24 hours. Similar cytotoxicity was not observed in lung and breast carcinoma cell lines until 10 ng/ml and/or at later time-points, while normal fibroblasts, myeloma, and prostate carcinoma cell lines were much more resistant to drug treatment. The apoptotic population of monolayer SYO-1 and Fuji cells time-dependently increased to 83.1% and 85.2%, respectively, at 1 ng/ml following 72 hours. Three-dimensional spheroid cultures, intrinsically resistant to chemotherapy, also demonstrated effective synovial sarcoma cell death by depsipeptide at ng/ml concentrations. Conclusion: The molecular biology of synovial sarcoma suggests it may be sensitive to chromatin remodeling agents. The histone deacetylase inhibitor depsipeptide causes apoptosis-mediated cell death in human synovial sarcoma monolayer and spheroidal cell lines at very low, clinically-achievable concentrations. No significant financial relationships to disclose.