Abstract
We studied the unique inhibitor of the histone deacetylases (HDAC) valproate-valpromide of acyclovir (AN446) that upon metabolic degradation release the HDAC inhibitor (HDACI) valproic acid (VPA). Among the HDAC inhibitors that we have tested, only AN446, and to a lesser extent VPA, synergized with doxorubicin (Dox) anti-cancer activity. Romidepsin (Rom) was additive and the other HDACIs tested were antagonistic. These findings led us to test and compare the anticancer activities of AN446, VPA, and Rom with and without Dox in the 4T1 triple-negative breast cancer murine model. A dose of 4 mg/kg once a week of Dox had no significant effect on tumor growth. Rom was toxic, and when added to Dox the toxicity intensified. AN446, AN446 + Dox, and VPA + Dox suppressed tumor growth. AN446 and AN446 + Dox were the best inhibitory treatments for tumor fibrosis, which promotes tumor growth and metastasis. Dox increased fibrosis in the heart and kidneys, disrupting their function. AN446 most effectively suppressed Dox-induced fibrosis in these organs and protected their function. AN446 and AN446 + Dox treatments were the most effective inhibitors of metastasis to the lungs, as measured by the gap area. Genes that control and regulate tumor growth, DNA damage and repair, reactive oxygen production, and generation of inflammation were examined as potential therapeutic targets. AN446 affected their expression in a tissue-dependent manner, resulting in augmenting the anticancer effect of Dox while reducing its toxicity. The specific therapeutic targets that emerged from this study are discussed.
Highlights
Acetylation of histones plays an important role in cancer development and progression
Class I enzymes are potential specific targets, we searched for effective combinations of leading histone deacetylases (HDACs) inhibitor (HDACI) that would augment the therapeutic impact of Dox
Prior to in vivo studies, we examined the nature of the interaction between the leading HDACIs to Dox on murine triple-negative breast cancer (TNBC) 4T1 cells
Summary
Acetylation of histones plays an important role in cancer development and progression. The disrupted expression of HDACs in cancer cells changes their epigenetics and protects them from genotoxic stress, granting them a survival advantage. HDAC isoenzymes class I have been shown to be strongly expressed in more aggressive breast cancer (BC) types [3,4]. A structurally diverse group of HDAC inhibitory molecules exhibiting pleiotropic cytotoxic effects on various cancer cells in vitro and in vivo were described [1,2,3,4]. SAHA, belinostat, panobinostat, and the cyclic peptide, romidepsin, were approved by the FDA for the treatment of cancer [1,2]. The HDAC inhibitor valproic acid (VPA), alone and in combination with anticancer agents, has exhibited therapeutic activity in various cancer indications including metastatic BC [5,6]
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