A rationally designed histone deacetylase inhibitor with distinct antitumor activity against ovarian cancer

Ya Ting Yang, Curt Balch, Samuel K. Kulp, Michael R. Mand, Kenneth P. Nephew, Ching Shih Chen

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Histone deacetylase inhibitors (HDACIs) are a class of antineoplastic agents previously demonstrating preclinical chemosensitizing activity against drug-resistant cancer cells and mouse xenografts. However, whereas clinical studies have shown efficacy against human hematologic malignancies, solid tumor trials have proved disappointing. We previously developed a novel HDACI, "OSU-HDAC42," and herein examine its activity against ovarian cancer cell lines and xenografts. OSU-HDAC42, (i) unlike most HDACIs, elicited a more than five-fold increase in G2-phase cells, at 2.5 μM, with G 2 arrest followed by apoptosis; (ii) at 1.0 μM, completely repressed messenger RNA expression of the cell cycle progression gene cdc2; (iii) at low doses (0.25-1.0 μM for 24 hours), induced tumor cell epithelial differentiation, as evidenced by morphology changes and a more than five-fold up-regulation of epithelium-specific cytokeratins; (iv) potently abrogated the growth of numerous ovarian cancer cells, with IC50 values of 0.5 to 1.0 μM, whereas also remaining eight-fold less toxic (IC50 of 8.6 μM) to normal ovarian surface epithelial cells; and (v) chemosensitizated platinum-resistant mouse xenografts to cisplatin. Compared with the clinically approved HDACI suberoylanilide hydroxamic acid (vorinostat), 1.0 μM OSU-HDAC42 was more biochemically potent (i.e., enzyme-inhibitory), as suggested by greater gene up-regulation and acetylation of both histone and nonhistone proteins. In p53-dysfunctional cells, however, OSU-HDAC42 was two- to eight-fold less inductive of p53-regulated genes, whereas also having a two-fold higher IC50 than p53-functional cells, demonstrating some interaction with p53 tumor-suppressive cascades. These findings establish OSU-HDAC42 as a promising therapeutic agent for drug-resistant ovarian cancer and justify its further investigation.

Original languageEnglish (US)
Pages (from-to)552-563
Number of pages12
JournalNeoplasia
Volume11
Issue number6
DOIs
StatePublished - Jun 2009

ASJC Scopus subject areas

  • Cancer Research

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