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Research Articles: Therapeutics, Targets, and Development

Synergistic activity of the histone deacetylase inhibitor suberoylanilide hydroxamic acid and the bisphosphonate zoledronic acid against prostate cancer cells in vitro

¹ Research Center of Pharmacology and Experimental Therapeutics and ² Department of Pediatric Oncology/Hematology, Ernst Moritz Arndt University, Greifswald, Germany

Requests for reprints: Jürgen Sonnemann, Institut für Pharmakologie, Abteilung für Pädiatrische Onkologie und Hämatologie, Universität Greifswald, Friedrich-Loeffler-Str. 23d, D-17487 Greifswald, Germany. Phone: 49-3834-865653; Fax: 49-3834-865617. E-mail: juergen.sonnemann{at}uni-greifswald.de

Abstract

Bisphosphonates are widely used agents for the treatment of malignant bone disease. They inhibit osteoclast-mediated bone resorption and can have direct effects on cancer cells. In this study, we investigated whether the anticancer activity of the third-generation bisphosphonate zoledronic acid (ZOL) could be enhanced by combination with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). We found that ZOL and SAHA cooperated to induce cell death in the prostate cancer cell lines LNCaP and PC-3. The effect was synergistic, as evidenced by combination index isobologram analysis. ZOL and SAHA synergized to induce dissipation of the mitochondrial transmembrane potential, to activate caspase-3, and to trigger DNA fragmentation, showing that the combination of ZOL and SAHA resulted in the initiation of apoptosis. Because ZOL acts by inhibiting the mevalonate pathway, thereby preventing protein prenylation, we explored whether the mevalonate pathway was also the target of the cooperative action of ZOL and SAHA. We found that geranylgeraniol, but not farnesol, significantly reduced ZOL/SAHA-induced cell death, indicating that the synergistic action of the agents was due to the inhibition of geranylgeranylation. Consistently, a direct inhibitor of geranylgeranylation, GGTI-298, synergized with SAHA to induce cell death, whereas an inhibitor of farnesylation, FTI-277, had no effect. In addition, SAHA synergized with mevastatin, an inhibitor of the proximal enzyme in the mevalonate pathway. These in vitro findings provide a rationale for an in vivo exploration into the potential of combining SAHA and ZOL, or other inhibitors of the mevalonate pathway, as an effective strategy for anticancer therapy. [Mol Cancer Ther 2007;6(11):2976–84]

Grant support: Wilhelm Sander-Stiftung, Neustadt/Donau, Germany.

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.

³ Supplementary data for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 3/29/07; revised 8/ 8/07; accepted 10/ 1/07.