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Synergistic Interaction between Histone Deacetylase and Topoisomerase II Inhibitors Is Mediated through Topoisomerase IIß

Authors' Affiliation: Experimental Therapeutics Program, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida

Requests for reprints: Pamela N. Munster, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, MRC 4E, Tampa, FL 33612. Phone: 813-745-8948; Fax: 813-745-1984; E-mail: Munstepn{at}moffitt.usf.edu.

Background: DNA topoisomerase II inhibitors and poisons are among the most efficacious drugs for the treatment of cancer. Sensitivity of cancer cells to the cytotoxic effects of topoisomerase II targeting agents is thought to depend on the expression of the topoisomerase II isoform, and drug resistance is often associated with loss or mutation of topoisomerase II. Histone deacetylase inhibitors (HDACi) are a novel class of compounds that potentiate the antitumor effects of topoisomerase II–targeting agents.

Methods: The interaction between HDACi and topoisomerase II–targeting agents in cancer cells was evaluated as a function of topoisomerase II and topoisomerase IIß expression. Topoisomerase II isoforms were selectively depleted using small interfering RNA and antisense. Drug-induced formation of cleavable complexes involving topoisomerase II and topoisomerase IIß was evaluated by trapped-in-agarose DNA immunostaining and band depletion assays in the presence and absence of HDACi.

Results: Preexposure to HDACi increased the cytotoxicity of topoisomerase II poisons. This was associated with a down-regulation of topoisomerase II expression but had no effects on topoisomerase IIß. In the setting of HDACi-induced chromatin decondensation and topoisomerase II depletion, topoisomerase II poison cytotoxicity was mediated through topoisomerase IIß cleavable complex formation. The HDACi-induced sensitization was also observed in cells with target-specific resistance to topoisomerase II poisons.

Conclusions: The recruitment of topoisomerase IIß as a target may overcome primary or emergent drug resistance to topoisomerase II–targeting agents and hence may broaden the applicability of this important class of anticancer agents.

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