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[Cancer Research 63, 7291-7300, November 1, 2003]
© 2003 American Association for Cancer Research

Regular Articles

Inhibition of Histone Deacetylase Increases Cytotoxicity to Anticancer Drugs Targeting DNA1

Myoung Sook Kim, Mellissa Blake, Jin Hyen Baek, Glenda Kohlhagen, Yves Pommier and France Carrier2

Biochemistry and Molecular Biology Department, School of Medicine, University of Maryland, Baltimore, Maryland 21201-1503 [M. S. K., M. B., F. C.]; Johns Hopkins University, Baltimore, Maryland 21231 [J. H. B.]; and National Cancer Institute, NIH, Bethesda, Maryland 20892 [G. K., Y. P.]

Several anticancer drugs target DNA or enzymes acting on the DNA. Because chromatin DNA is tightly compacted, accessibility to the drug target may reduce the efficiency of these anticancer drugs. We thus treated four human cancer cell lines and two normal epithelial cell lines with either trichostatin A (TSA) or SAHA, two histone deacetylase inhibitors, before exposing the cells to VP-16, ellipticine, camptothecin, doxorubicin, cisplatin, 5-fluorouracil, or cyclophosmamide. Pretreatment with TSA or SAHA increased the killing efficiency of VP-16, ellipticine, doxorubicin, and cisplatin. The magnitude of sensitization is cell type specific and is >10-fold for VP-16 in D54, a brain tumor cell line intrinsically resistant to topoisomerase II inhibitors. Topoisomerase II levels and activity were not affected by this treatment, but p53, p21, and Gadd45 protein levels were markedly induced. Moreover, pretreatment with TSA also increased VP-16-induced apoptosis in a p53-dependent and -independent manner. Treating the cells in the reverse order (anticancer drug first, followed by TSA or SAHA) had no more cytotoxic effect than the drug alone. These data suggest that loosening-up the chromatin structure by histone acetylation can increase the efficiency of several anticancer drugs targeting DNA. This may be advantageous for treating tumors intrinsically resistant to these drugs.




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