Disparate Impact of Butyroyloxymethyl Diethylphosphate AN-7, a Histone Deacetylase Inhibitor, and Doxorubicin in Mice Bearing a Mammary TumorReportar como inadecuado




Disparate Impact of Butyroyloxymethyl Diethylphosphate AN-7, a Histone Deacetylase Inhibitor, and Doxorubicin in Mice Bearing a Mammary Tumor - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

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.



Autor: Nataly Tarasenko, Suzanne M. Cutts, Don R. Phillips, Aida Inbal, Abraham Nudelman, Gania Kessler-Icekson, Ada Rephaeli

Fuente: http://plos.srce.hr/



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