The histone deacetylase inhibitor vorinostat selectively sensitizes fibrosarcoma cells to chemotherapy

Abstract

Soft tissue sarcoma (STS) is a rare malignancy that is generally resistant to chemotherapy. We investigated the ability of the histone deacetylase inhibitor vorinostat to sensitize STS cells versus normal fibroblasts to chemotherapy. Fibrosarcoma, leiomyosarcoma, and liposarcoma cells and normal fibroblasts were treated with vorinostat to determine effects on proliferation and basal apoptosis as measured by total cell number and cleaved caspase 3 staining. Effects on histone deacetylases (HDAC) activity were confirmed by Western blotting for acetylated histone H3. A clinically relevant dose of vorinostat that had no effect on basal apoptosis was selected to examine altered sensitivity to doxorubicin. The effects of vorinostat, doxorubicin, or the combination on fibrosarcoma growth in vivo were determined in a xenograft model. Tumor volume was measured biweekly and HDAC activity and cell death were assessed by immunohistochemical analysis of acetylated histone H3, cleaved caspase 3, and TUNEL staining. Vorinostat inhibited proliferation and induced histone acetylation without affecting basal apoptosis levels. Combined treatment with vorinostat and doxorubicin synergistically induced apoptosis in vitro in fibrosarcoma but not leiomyosarcoma, liposarcoma, or normal fibroblasts. In nude mice, the combination of vorinostat and doxorubicin inhibited fibrosarcoma xenograft growth further than either agent alone. Cell death, as measured by cleaved caspase 3 and TUNEL staining, was greatest in xenografts from mice treated with vorinostat and doxorubicin. Vorinostat inhibits growth and induces chemosensitivity in fibrosarcoma cells in vitro and in vivo, suggesting that the combination of vorinostat and chemotherapy may represent a novel treatment option for this STS subtype. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:623-632, 2011.

Therapeutic applications of histone deacetylase inhibitors in sarcoma

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Phase 1 study of oral abexinostat, a histone deacetylase inhibitor, in combination with doxorubicin in patients with metastatic sarcoma

“…Classic HDAC inhibitors, such as vorinostat 6 and valproate 7 were observed to exert a growth inhibitory effect sarcoma cell lines. These HDAC inhibitors were also observed to sensitize fibrosarcoma 11 , osteosarcoma 13 , and chondrosarcoma 14 cell lines to chemotherapy.…”

Vorinostat with sustained exposure and high solubility in poly(ethylene glycol)‐b‐poly(dl‐lactic acid) micelle nanocarriers: Characterization and effects on pharmacokinetics in rat serum and urine

“…6,7 Vorinostat is marketed by Merck & Co., Inc. as an oral capsule under the brand name Zolinza ® . 5 Although the therapeutic potential of vorinostat is great 8,9,10 , vorinostat is plagued by poor aqueous solubility (0.2 mg/ml) and low permeability (a log partition coefficient of 1.9) as indicated by its Class IV designation in Biopharmaceutics Classification System (BCS). 11 Because of this, development of a parenteral formulation of vorinostat has been hindered.…”