Comparison of the anticancer properties of a novel valproic acid prodrug to leading histone deacetylase inhibitors

Nataly Tarasenko, Hanna Chekroun-Setti, Abraham Nudelman, Ada Rephaeli

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


The HDAC inhibitory activity of valproic acid (VPA) has led to on-going evaluation of it as an anticancer agent. The histone deacetylase (HDAC) inhibitor AN446, a prodrug of VPA, releases the acid upon metabolic degradation. AN446 is >60-fold more potent than VPA in killing cancer cells in vitro. Herein, we compare the activities of AN446, as an anticancer agent, to those of representative types from each of the four major classes of HDAC inhibitors (HDACIs): vorinostat, romidepsin, entinostat, and VPA. AN446 exhibited the greatest selectivity and HDAC inhibitory activity against cancer cells. In glioblastoma cells only AN446, and in MDA-MB-231 cells only AN446 and VPA interacted in synergy with doxorubicin (Dox). AN446 was superior to the studied HDACIs in inducing DNA-damage in cancer cells, while in normal astrocytes and cardiomyoblasts AN446 was the least toxic. AN446 was the only HDACI tested that exhibited selective HDAC inhibitory activity that was high in cancer cells and low in noncancerous cells. This discriminating inhibition correlated with the toxicity of the HDACIs, suggesting that their effects could be attributed to HDAC inhibition. In cardiomyoblasts, the HDACIs tested, except for AN446, hampered DNA repair by reducing the level of Rad 51. VPA and AN446 were the most effective HDACIs in inhibiting in vitro migration and invasion. The advantages of AN446 shown here, position it as a potentially improved HDACI for treatment of glioblastoma and triple negative breast cancer.

Original languageEnglish
Pages (from-to)3417-3428
Number of pages12
JournalJournal of Cellular Biochemistry
Issue number4
StatePublished - Apr 2018

Bibliographical note

Funding Information:
Tel Aviv University Special Funds; Israel Cancer Research Fund USA, Grant number: 0601564411; The Bar Ilan University Marcus Center for Medicinal Chemistry (AN); Masa Program, the Jewish Agency (H C-S)

Publisher Copyright:
© 2017 Wiley Periodicals, Inc.


  • HDAC inhibitors
  • breast carcinoma
  • doxorubicin
  • glioblastoma
  • prodrug
  • valproic acid


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