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Departments of ¹ Medicine and ² Pathology, Laboratory for Molecular Oncology, LDS Hospital, Salt Lake City, Utah

Requests for reprints: Kevin A. Strait, Cancer Research Laboratory, Department of Medicine, LDS Hospital, 325 8th Avenue, Salt Lake City, UT 84143. Phone: 801-408-1558; Fax: 801-408-5822. E-mail: ldkstrai{at}ihc.com

Trichostatin A produces predominantly G₁ cell-cycle blockade and differentiation of the cisplatinum-sensitive A2780 ovarian cancer cell line. Given the propensity of ovarian tumors to become resistant to cisplatinum, often leading to cross-resistance to other agents, we have extended these observations by examining how the emergence of resistant phenotypes in A2780 cells affects the actions of histone deacetylase (HDAC) inhibitors. Trichostatin A exposure (100 ng/mL, 24 hours) induced ultrastructural differentiation of the "intrinsically" cisplatinum-resistant A2780-9M subline, with the reappearance of intercellular junctions and lumina containing primitive microvilli. Similar trichostatin A exposure in the acquired resistance A2780CP cells produced minimal differentiation consisting of occasional weak intercellular junctions. Independent of the differences in trichostatin A–induced differentiation, in both resistant sublines trichostatin A produced a similar reduction in cell viability, by >90%, within 5 days of treatment. Diminished viability in both A2780-9M and CP cells was associated with the absence of cell cycle arrest in G₁, resulting in predominant G₂-checkpoint arrest accompanied by a 10- to 20-fold increase in Annexin V binding and the reemergence of apoptosis. Similar cell cycle arrests and apoptosis were also observed using other HDAC inhibitors and in other resistant ovarian cancer cell lines (OVCAR-3 and SK-OV-3). Trichostatin A–induced apoptosis in resistant cells is in sharp contrast to its effects on the parental cisplatinum-sensitive A2780 and normal MRC-5 fibroblast cell lines (predominant cycle arrest in G₁ with no detectable apoptosis). Western immunoblot analysis indicated trichostatin A triggers apoptosis in resistant ovarian cancer cells via p53-independent activation of the intrinsic "mitochondrial" pathway, commensurate with induction of the Bcl-2–related protein Bad. These results suggest cisplatinum resistance alters the effects of HDAC inhibition through a shift in cell cycle arrest from the G₁ to the G₂ checkpoint and reactivation of the intrinsic mitochondrial apoptotic cascade.

Key Words: Trichostatin A • Resistance • Ovarian • Histone Deacetylase • Cisplatinum • Bad

Grant support: Feature Films for Families Cancer Research Fund (CEO: Forrest S. Baker III), The Smith Cancer Institute, The Joni Spafford Whitney Endowment, Warren and Kay Forsythe, The Annette Montgomery Bourne Endowment, and The Deseret Foundation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 4/26/04; revised 12/20/04; accepted 1/28/05.

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