1. Decitabine and suberoylanilide hydroxamic acid (SAHA) inhibit growth of ovarian cancer cell lines and xenografts while inducing expression of imprinted tumor suppressor genes, apoptosis, G2/M arrest, and autophagy.
- Author
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Chen MY, Liao WS, Lu Z, Bornmann WG, Hennessey V, Washington MN, Rosner GL, Yu Y, Ahmed AA, and Bast RC Jr
- Subjects
- Animals, Antimetabolites, Antineoplastic pharmacology, Azacitidine pharmacology, Cell Division drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Decitabine, Drug Synergism, Drug Therapy, Combination, Epigenomics, Female, G2 Phase drug effects, Gene Expression Regulation, Neoplastic drug effects, Histone Deacetylase Inhibitors pharmacology, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Transplantation, Heterologous, Vorinostat, Apoptosis drug effects, Autophagy, Azacitidine analogs & derivatives, Genes, Tumor Suppressor drug effects, Genomic Imprinting, Hydroxamic Acids pharmacology, Ovarian Neoplasms drug therapy
- Abstract
Background: Epigenetic therapy has had a significant impact on the management of hematologic malignancies, but its role in the treatment of ovarian cancer remains to be defined. The authors previously demonstrated that treatment of ovarian and breast cancer cells with DNA methyltransferase and histone deacetylase (HDAC) inhibitors can up-regulate the expression of imprinted tumor suppressors. In this study, demethylating agents and HDAC inhibitors were tested for their ability to induce re-expression of tumor suppressor genes, inhibiting growth of ovarian cancer cells in culture and in xenografts., Methods: Ovarian cancer cells (Hey and SKOv3) were treated with demethylating agents (5-aza-20-deoxycytidine [DAC] or 5-azacitidine [AZA]) or with HDAC inhibitors (suberoylanilide hydroxamicacid [SAHA] or trichostatin A [TSA]) to determine their impact on cellular proliferation, cell cycle regulation, apoptosis, autophagy, and re-expression of 2 growth inhibitory imprinted tumor suppressor genes: guanosine triphosphate-binding Di-RAS-like 3 (ARHI) and paternally expressed 3 (PEG3). The in vivo activities of DAC and SAHA were assessed in a Hey xenograft model., Results: The combination of DAC and SAHA produced synergistic inhibition of Hey and SKOv3 cell growth by apoptosis and cell cycle arrest. DAC induced autophagy in Hey cells that was enhanced by SAHA. Treatment with both agents induced re-expression of ARHI and PEG3 in cultured cells and in xenografts, correlating with growth inhibition. Knockdown of ARHI decreased DAC-induced autophagy. DAC and SAHA inhibited the growth of Hey xenografts and induced autophagy in vivo., Conclusions: A combination of DAC and SAHA inhibited ovarian cancer growth while inducing apoptosis, G2/M arrest, autophagy, and re-expression of imprinted tumor suppressor genes., (Cancer © 2011 American Cancer Society.)
- Published
- 2011
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