Potential of histone deacetylase inhibitors in the control and regulation of prostate, breast and ovarian cancer

Abstract

Histone deacetylases (HDACs) are enzymes that play a role in chromatin remodeling and epigenetics. They belong to a specific category of enzymes that eliminate the acetyl part of the histones’ -N-acetyl lysine, causing the histones to be wrapped compactly around DNA. Numerous biological processes rely on HDACs, including cell proliferation and differentiation, angiogenesis, metastasis, gene regulation, and transcription. Epigenetic changes, specifically increased expression and activity of HDACs, are commonly detected in cancer. As a result, HDACi could be used to develop anticancer drugs. Although preclinical outcomes with HDACs as monotherapy have been promising clinical trials have had mixed results and limited success. In both preclinical and clinical trials, however, combination therapy with different anticancer medicines has proved to have synergistic effects. Furthermore, these combinations improved efficacy, decreased tumor resistance to therapy, and decreased toxicity. In the present review, the detailed modes of action, classification of HDACs, and their correlation with different cancers like prostate, breast, and ovarian cancer were discussed. Further, the different cell signaling pathways and the structure-activity relationship and pharmaco-toxicological properties of the HDACi, and their synergistic effects with other anticancer drugs observed in recent preclinical and clinical studies used in combination therapy were discussed for prostate, breast, and ovarian cancer treatment.

Sodium butyrate supresses malignant human mast cell proliferation, downregulates expression of KIT and promotes differentiation

“…4 Ratio of C-KIT expression of cells treated with 100 µM NaBu for 4 days, compared to untreated cells. 5 Ratio of C-KIT expression of cells treated with 100 µM NaBu for 3 days, compared to untreated cells. 6 Ratio of C-KIT expression of cells treated with 100 µM NaBu for 3 days, compared to untreated cells.…”

“…Mutation and/or aberrant expression of HDACs is often observed in numerous human cancers, making them anti-cancer therapeutic targets (4). HDAC inhibitors (HDACi) are a class of drugs that cause phenotypic changes in transformed cells (5), including growth arrest by disrupting the expression of numerous genes (1), yet most of the currently approved HDACi are wide-spectrum with poor clinical outcomes and numerous side-effects (6).…”

From HDAC to Voltage-Gated Ion Channels: What’s Next? The Long Road of Antiepileptic Drugs Repositioning in Cancer

“…Similarly, HDACs have also been found aberrantly expressed in ovarian [ 49 , 198 ] and endometrial [ 199 ] cancer, NSCLC [ 200 , 201 ], brain tumors [ 202 ] and hematologic malignancies [ 203 ], including multiple myeloma [ 204 ].…”

“…Thus, reactivation of TS genes transcription by means of HDAC inhibitors (HDACi) treatment might be responsible for the observed arrest in cell growth, block in cell cycle progression and induction of apoptosis, although HDACi may also trigger other molecular events, including generation of reactive oxygen species (ROS) and inhibition of angiogenesis [ 45 ]. Extensive literature and numerous reviews continuously offer interesting and deep insight into HDACs classification, activity, role in cancer and therapeutic implications [ 46 , 47 , 48 , 49 ].…”

Design and synthesis of bioreductive prodrugs of class I histone deacetylase inhibitors and their biological evaluation in virally transfected acute myeloid leukemia cells

“…[6,7] Several HDAC inhibitors (HDACi) have been developed and tested as potential therapies for solid tumors and blood malignancies. [8][9][10] Most HDACi share a common pharmacophoric feature consisting of three distinct groups as follows: a zincbinding group (ZBG), a capping group, and a linker. [11] The ZBG is responsible for chelating Zn 2+ ion in the active site of HDACs.…”