Inhibition of Histone Deacetylase Increases Cytotoxicity to Anticancer Drugs Targeting DNA

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7291-7300
Number of pages10
JournalCancer Research
Volume63
Issue number21
StatePublished - Nov 1 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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