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Research Articles: Therapeutics, Targets, and Development

Histone deacetylase inhibitors and paclitaxel cause synergistic effects on apoptosis and microtubule stabilization in papillary serous endometrial cancer cells

¹ Department of Obstetrics and Gynecology, ² Mayo Comprehensive Cancer Center, Mayo Clinic and Foundation, Rochester, Minnesota; ³ Shandong Provincial Hospital, Jinan, China; and ⁴ Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China

Requests for reprints: Sean C. Dowdy, Division of Gynecologic Surgery, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-266-3536; Fax: 507-266-9300. E-mail: dowdy.sean{at}mayo.edu

Abstract

The use of histone deacetylase (HDAC) inhibitors has shown promise for a variety of malignancies. In this investigation, we define the activity of this class of inhibitors in combination with traditional cytotoxic chemotherapy in endometrial cancer cells. Significant reductions in growth were observed in Ark2 and KLE endometrial cancer cells following treatment with paclitaxel, doxorubicin, carboplatin, or the HDAC inhibitor trichostatin A (TSA). However, only combined treatment with TSA/paclitaxel caused synergistic inhibition of cell growth. This combination also resulted in significant changes in cell morphology. Using cell cycle analysis, nuclear staining, and Western blot analysis for poly(ADP-ribose) polymerase and caspase-9 degradation products, TSA/paclitaxel showed the most dramatic activation of the apoptotic cascade. These effects were also observed when the HDAC inhibitors HDAC inhibitor-1 or oxamflatin were substituted for TSA. The anticancer properties of paclitaxel are known to result in part from inhibition of microtubule depolymerization, which results in apoptosis. We show that TSA administration also stabilizes microtubules via -tubulin acetylation. Furthermore, using Western blot and immunohistochemical analysis, treatment with TSA/paclitaxel led to a significant increase in acetylated tubulin and microtubule stabilization. These effects were confirmed in a mouse xenograft model. Moreover, TSA/paclitaxel resulted in a 50% reduction in tumor weight compared with either agent alone. This study provides in vivo evidence of nonhistone protein acetylation as one possible mechanism by which HDAC inhibitors reduce cancer growth. The TSA/paclitaxel combination seems to hold promise for the treatment of serous endometrial carcinoma and other malignancies with limited sensitivity to paclitaxel. [Mol Cancer Ther 2006;5(11):2767–76]

Grant support: Mayo Clinic Comprehensive Cancer Center.

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.

Note: S.C. Dowdy, S. Jiang, and X.C. Zhou contributed equally to this work.

Received 4/18/06; revised 8/ 9/06; accepted 9/25/06.

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