Premium
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(s) -
Chen MinYu,
Liao Warren S.L.,
Lu Zhen,
Bornmann William G.,
Hennessey Violeta,
Washington Michele N.,
Rosner Gary L.,
Yu Yinhua,
Ahmed Ahmed Ashour,
Bast Robert C.
Publication year - 2011
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.26073
Subject(s) - trichostatin a , cancer research , demethylating agent , autophagy , ovarian cancer , cell growth , apoptosis , histone deacetylase , cancer cell , cell cycle checkpoint , cell cycle , growth inhibition , chemistry , biology , cancer , medicine , dna methylation , gene expression , histone , biochemistry , gene
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‐2′‐deoxycytidine [DAC] or 5‐azacitidine [AZA]) or with HDAC inhibitors (suberoylanilide hydroxamic acid [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;. © 2011 American Cancer Society.