Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2014, 158(2):161-169 | DOI: 10.5507/bp.2013.085

Histone deacetylase inhibitors in cancer therapy. A review

Jan Hrabeta^a, Marie Stiborova^b, Vojtech Adam^c,d, Rene Kizek^c,d, Tomas Eckschlager^a

^a Department of Pediatric Hematology and Oncology, 2^nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic

^b Department of Biochemistry, Faculty of Science, Charles University in Prague, Prague

^c Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Brno

^d Central European Institute of Technology, University of Technology, Brno

Background: Despite recent success toward discovery of more effective anticancer drugs, chemoresistance remains a major cause of treatment failure. There is emerging evidence that epigenetics plays a key role in the development of the resistance. Epigenetic regulators such as histone acetyltransferases (HATs) and histone deacetylases (HDACs) play an important role in gene expression. The latter are found to be commonly linked with many types of cancers and influence cancer development. Overall, histone acetylation is being investigated as a therapeutic target because of its importance in regulating gene expression. This review summarizes mechanisms of the anticancer effects of histone deacetylase (HDAC) inhibitors and the results of clinical studies.

Results: Different HDAC inhibitors induce cancer cell death by different mechanisms that include changes in gene expression and alteration of both histone and non-histone proteins. Enhanced histone acetylation in tumors results in modification of expression of genes involved in cell signaling. Inhibition of HDACs causes changed expression in 2-10 % of genes involved in important biological processes. The results of experiments and clinical studies demonstrate that combination of HDAC inhibitors with some anticancer drugs have synergistic or additive effects.

Conclusions: Even though many biological effects of HDAC inhibitors have been found, most of the mechanisms of their action remain unclear. In addition, their use in combination with other drugs and the combination regime need to be investigated. The discovery of predictive factors is also necessary. Finally, a key question is whether the pan-HDAC inhibitors or the selective inhibitors will be more efficient for different types of cancers.

Keywords: chromatin remodeling, histone acetylation, histone deacetylases, histone deacetylase inhibitors, combined treatment modalities, mechanisms of combined treatment

Received: July 3, 2013; Accepted: November 12, 2013; Prepublished online: November 21, 2013; Published: June 23, 2014  Show citation