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 Nephew, Ching Shih Chen

Research output: Contribution to journalArticle

38 Citations (Scopus)

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

Fingerprint

Histone Deacetylase Inhibitors
Ovarian Neoplasms
Heterografts
Inhibitory Concentration 50
Neoplasms
Up-Regulation
cdc Genes
G2 Phase
Poisons
p53 Genes
Hematologic Neoplasms
Acetylation
Keratins
Platinum
Pharmaceutical Preparations
Antineoplastic Agents
Histones
Cisplatin
Cell Differentiation
Epithelium

ASJC Scopus subject areas

  • Cancer Research

Cite this

A rationally designed histone deacetylase inhibitor with distinct antitumor activity against ovarian cancer. / Yang, Ya Ting; Balch, Curt; Kulp, Samuel K.; Mand, Michael R.; Nephew, Kenneth; Chen, Ching Shih.

In: Neoplasia, Vol. 11, No. 6, 06.2009, p. 552-563.

Research output: Contribution to journalArticle

Yang, Ya Ting ; Balch, Curt ; Kulp, Samuel K. ; Mand, Michael R. ; Nephew, Kenneth ; Chen, Ching Shih. / A rationally designed histone deacetylase inhibitor with distinct antitumor activity against ovarian cancer. In: Neoplasia. 2009 ; Vol. 11, No. 6. pp. 552-563.
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