The histone deacetylase inhibitor butyroyloxymethyl diethylphosphate (AN-7) protects normal cells against toxicity of anticancer agents while augmenting their anticancer activity

Nataly Tarasenko, Gania Kessler-Icekson, Pnina Boer, Aida Inbal, Hadassa Schlesinger, Don R. Phillips, Suzanne M. Cutts, Abraham Nudelman, Ada Rephaeli

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) has been shown to synergize doxorubicin (Dox) anticancer activity while attenuating its cardiotoxicity. In this study we further explored the selectivity of AN-7's action in several cancer and normal cells treated with anticancer agents. The cells studied were murine mammary 4T1, human breast T47D and glioblastoma U251 cancer cell lines, neonatal rat cardiomyocytes, cardiofibroblasts and astrocytes, and immortalized cardiomyocyte H9C2 cells. Cell death, ROS production and changes in protein expression were measured and in vivo effects were evaluated in Balb-c mice. AN-7 synergized Dox and anti-HER2 cytotoxicity against mammary carcinoma cells with combination indices of 0.74 and 0.79, respectively, while it protected cardiomyocytes against their toxicity. Additionally AN-7 protected astrocytes from Dox-cytoxicity. Cell-type specific changes in the expression of proteins controlling survival, angiogenesis and inflammation by AN-7 or AN-7+Dox were observed. In mice, the protective effect of AN-7 against Dox cardiotoxicity was associated with a reduction in inflammatory factors. In summary, AN-7 augmented the anticancer activity of Dox and anti-HER2 and attenuated their toxicity against normal cells. AN-7 modulation of c- Myc, thrombospondin-1, lo-FGF-2 and other proteins were cell type specific. The effects of AN-7, Dox and their combination were preserved in vivo indicating the potential benefit of combining AN-7 and Dox for clinical use.

Original languageEnglish
Pages (from-to)130-143
Number of pages14
JournalInvestigational New Drugs
Volume30
Issue number1
DOIs
StatePublished - Feb 2012

Bibliographical note

Funding Information:
Acknowledgments We thank Ms. S. Dominitz for editorial assistance. This work was supported in part by grants from The Israel Cancer Association (Grant No 20092001, Israel); Teva Special Funds (Dr. A. Swartz) and The Marcus Center for Pharmaceutical and Medicinal Chemistry at Bar Ilan University, Ramat Gan, Israel. Nataly Tarasenko carried out this work as part of the requirements for a PhD degree from the Department of Hematology, Sackler School of Medicine, Tel-Aviv University, Israel.

Keywords

  • Astrocytes
  • Cardiofibroblasts
  • Cardiomyocytes
  • Doxorubicin
  • HDAC inhibitor
  • HER2
  • Mammary carcinoma

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