synergism of heat shock protein 90 and histone deacetylase inhibitors in synovial sarcoma合作的热休克蛋白90和组蛋白脱乙酰酶抑制剂在滑膜肉瘤.pdfVIP

Hindawi Publishing Corporation Sarcoma Volume 2009, Article ID 794901, 10 pages doi:10.1155/2009/794901 Research Article Synergism of Heat Shock Protein 90 and Histone Deacetylase Inhibitors in Synovial Sarcoma Anne Nguyen,1 Le Su,1 Belinda Campbell,2 Neal M. Poulin,1 and Torsten O. Nielsen1 1Jack Bell Research Centre, Vancouver Coastal Health Research Institute, The University of British Columbia, 553 - 2660 Oak Street, Vancouver, BC, Canada V6H3Z6 2 Department of Radiation Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver, BC, Canada V5Z4E6 Correspondence should be addressed to Torsten O. Nielsen, torsten@interchange.ubc.ca Received 3 September 2008; Revised 2 January 2009; Accepted 18 January 2009 Recommended by Marcus Schlemmer Current systemic therapies have little curative benefit for synovial sarcoma. Histone deacetylase (HDAC) inhibitors and the heat shock protein 90 (Hsp90) inhibitor 17-AAG have recently been shown to inhibit synovial sarcoma in preclinical models. We tested combinations of 17-AAG with the HDAC inhibitor MS-275 for synergism by proliferation and apoptosis assays. The combination was found to be synergistic at multiple time points in two synovial sarcoma cell lines. Previous studies have shown that HDAC inhibitors not only induce cell death but also activate the survival pathway NF-κB, potentially limiting therapeutic benefit. As 17- AAG inhibits activators of NF-κB, we tested if 17-AAG synergizes with MS-275 through abrogating NF-κB activation. In our assays, adding 17-AAG blocks NF-κB activation by MS-275 and siRNA directed against histone deacetylase 3 (HDAC3) recapitulates the effects of MS-275. Additionally, we find that the NF-κB inhibitor BAY 11-7085 synergizes with MS-275. We conclude that agents inhibiting NF-κB synergize with HDA