RGD Reference Report - Disparate impact of butyroyloxymethyl diethylphosphate (AN-7), a histone deacetylase inhibitor, and doxorubicin in mice bearing a mammary tumor. - Rat Genome Database

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Disparate impact of butyroyloxymethyl diethylphosphate (AN-7), a histone deacetylase inhibitor, and doxorubicin in mice bearing a mammary tumor.

Authors: Tarasenko, N  Cutts, SM  Phillips, DR  Inbal, A  Nudelman, A  Kessler-Icekson, G  Rephaeli, A 
Citation: Tarasenko N, etal., PLoS One. 2012;7(2):e31393. doi: 10.1371/journal.pone.0031393. Epub 2012 Feb 23.
RGD ID: 7240549
Pubmed: PMID:22384017   (View Abstract at PubMed)
PMCID: PMC3285631   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0031393   (Journal Full-text)

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 gammaH2AX, 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 gammaH2AX 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 gammaH2AX 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Objects Annotated

Genes (Rattus norvegicus)
H2ax  (H2A.X variant histone)
Myc  (MYC proto-oncogene, bHLH transcription factor)
Rad51  (RAD51 recombinase)

Genes (Mus musculus)
H2ax  (H2A.X variant histone)
Myc  (myelocytomatosis oncogene)
Rad51  (RAD51 recombinase)

Genes (Homo sapiens)
H2AX  (H2A.X variant histone)
MYC  (MYC proto-oncogene, bHLH transcription factor)
RAD51  (RAD51 recombinase)


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