title: Disparate impact of butyroyloxymethyl diethylphosphate (AN-7), a histone deacetylase inhibitor, and doxorubicin in mice bearing a mammary tumor.
abstract: The histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) synergizes the cytotoxic effect of doxorubicin (Dox) and anti-HER2 on mammary carcinoma cells while protecting normal cells against their insults. This study investigated the concomitant changes occurring in heart tissue and tumors of mice bearing a subcutaneous 4T1 mammary tumor following treatment with AN-7, Dox, or their combination. Dox or AN-7 alone led to inhibition of both tumor growth and lung metastases, whereas their combination significantly increased their anticancer efficacy and attenuated Dox- toxicity. Molecular analysis revealed that treatment with Dox, AN-7, and to a greater degree, AN-7 together with Dox increased tumor levels of γH2AX, the marker for DNA double-strand breaks and decreased the expression of Rad51, a protein needed for DNA repair. These events culminated in increased apoptosis, manifested by the appearance of cytochrome-c in the cytosol. In the myocardium, Dox-induced cardiomyopathy was associated with an increase in γH2AX expression and a reduction in Rad51 and MRE11 expression and increased apoptosis. The addition of AN-7 to the Dox treatment protected the heart from Dox insults as was manifested by a decrease in γH2AX levels, an increase in Rad51 and MRE11 expression, and a diminution of cytochrome-c release. Tumor fibrosis was high in untreated mice but diminished in Dox- and AN-7-treated mice and was almost abrogated in AN-7+Dox-treated mice. By contrast, in the myocardium, Dox alone induced a dramatic increase in fibrosis, and AN7+Dox attenuated it. The high expression levels of c-Kit, Ki-67, c-Myc, lo-FGF, and VEGF in 4T1 tumors were significantly reduced by Dox or AN-7 and further attenuated by AN-7+Dox. In the myocardium, Dox suppressed these markers, whereas AN-7+Dox restored their expression. In conclusion, the combination of AN-7 and Dox results in two beneficial effects, improved anticancer efficacy and cardioprotection.
authors.affiliation: Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Beilinson Campus, Petach-Tikva, Israel.
authors.forename: Nataly
authors.initials: N
authors.lastname: Tarasenko
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Cutts
authors.forename: Don R
authors.initials: DR
authors.lastname: Phillips
authors.forename: Aida
authors.initials: A
authors.lastname: Inbal
authors.forename: Abraham
authors.initials: A
authors.lastname: Nudelman
authors.forename: Gania
authors.initials: G
authors.lastname: Kessler-Icekson
authors.forename: Ada
authors.initials: A
authors.lastname: Rephaeli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008957:Models, Genetic; D009362:Neoplasm Metastasis; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species
chemical_list: D000970:Antineoplastic Agents; D002087:Butyrates; D005819:Genetic Markers; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; C502471:diethoxyphosphoryloxymethyl butanoate; C475961:gamma-H2AX protein, mouse; D004317:Doxorubicin