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

• Published in: Investigational new drugs 2012-02, Vol.30 (1), p.130-143
• Main Authors: Tarasenko, Nataly, Kessler-Icekson, Gania, Boer, Pnina, Inbal, Aida, Schlesinger, Hadassa, Phillips, Don R., Cutts, Suzanne M., Nudelman, Abraham, Rephaeli, Ada
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenic Proteins - metabolism; Animals; Antibodies; Antibodies - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - toxicity; Apoptosis; Astrocytes - drug effects; Astrocytes - pathology; Brain Neoplasms - enzymology; Brain Neoplasms - pathology; Breast cancer; Breast Neoplasms - enzymology; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Butyrates - pharmacology; Cardiomyocytes; Cardiotoxicity; Cell Line, Tumor; Cell Survival - drug effects; Cells; Cytoprotection; Cytotoxicity; Dose-Response Relationship, Drug; Doxorubicin - pharmacology; Drug dosages; Drug Synergism; Female; Fibroblasts - drug effects; Fibroblasts - pathology; Gene expression; Glioblastoma - enzymology; Glioblastoma - pathology; Growth factors; Histone Deacetylase Inhibitors - pharmacology; Humans; Inflammation Mediators - metabolism; Inhibitor drugs; Inhibitory Concentration 50; Laboratory animals; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - pathology; Oncology; Organophosphorus Compounds - pharmacology; Pharmacology; Pharmacology/Toxicology; Preclinical Studies; Proteins; Rats; Reactive Oxygen Species - metabolism; Receptor, ErbB-2 - immunology; Studies; Testing laboratories; Time Factors; Toxicity; Tumor necrosis factor-TNF
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-010-9542-z

Summary 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.