Synergistic interaction between histone deacetylase and topoisomerase II inhibitors is mediated through topoisomerase IIbeta.
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 IIalpha isoform, and drug resistance is often associated with loss or mutation of topoisomerase IIalpha. 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 IIalpha and topoisomerase IIbeta expression. Topoisomerase II isoforms were selectively depleted using small interfering RNA and antisense. Drug-induced formation of cleavable complexes involving topoisomerase IIalpha and topoisomerase IIbeta 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 IIalpha expression but had no effects on topoisomerase IIbeta. In the setting of HDACi-induced chromatin decondensation and topoisomerase IIalpha depletion, topoisomerase II poison cytotoxicity was mediated through topoisomerase IIbeta 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 IIbeta 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.
Marchion
Douglas C
DC
Experimental Therapeutics Program, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
Bicaku
Elona
E
Turner
Joel G
JG
Daud
Adil I
AI
Sullivan
Daniel M
DM
Munster
Pamela N
PN
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology; D002843:Chromatin / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D016373:DNA, Antisense / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004347:Drug Interactions; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008942:Mitoxantrone / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering / Q000494:pharmacology; D013713:Teniposide / Q000506:poisoning; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology
D000970:Antineoplastic Agents; D002087:Butyrates; D002843:Chromatin; D016373:DNA, Antisense; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; D059005:Topoisomerase II Inhibitors; C012589:trichostatin A; D014635:Valproic Acid; D013713:Teniposide; D008942:Mitoxantrone; D004250:DNA Topoisomerases, Type II