Histone Deacetylase Inhibitors In The Treatment Of Cancer: Overview And Perspectives

Abstract

Histone deacetylase inhibitors (HDACis) are one of the last frontiers in pharmaceutical research. Several classes of HDACi have been identified. Although more than 20 HDACi are under preclinical and clinical investigation as single agents and in combination therapies against different cancers, just two of them were approved by the US FDA: Zolinza(®) and Istodax(®), both licensed for the treatment of cutaneous T-cell lymphoma, the latter also of peripheral T-cell lymphoma. Since HDAC enzymes act by forming multiprotein complexes (clusters), containing cofactors, the main problem in designing new HDACi is that the inhibition activity evaluated on isolated enzyme isoforms does not match the in vivo outcomes. In the coming years, the research will be oriented toward a better understanding of the functioning of these protein complexes as well as the development of new screening assays, with the final goal to obtain new drug candidates for the treatment of cancer.

Phospho-ΔNp63α/microRNA network modulates epigenetic regulatory enzymes in squamous cell carcinomas

“…61,62 Using the knockdown approach, the highthroughput screening of HDAC showed that the class II HDACs, HDAC4 and HDAC9, regulate SMARCA2 expression. [61][62][63][64] We examined whether SMARCA2 expression was affected in SCC-11 cells and SCC-11M cells exposed to control media and 10 μg/ml cisplatin for 16 h (Fig. 4).…”

Multiple Roles of Autophagy in the Sorafenib Resistance of Hepatocellular Carcinoma

“…Combination of sorafenib with chloroquine significantly suppressed tumor growth compared with sorafenib alone [45, 47]. Vorinostat is the first histone deacetylases (HDAC) inhibitor to be approved for human clinical use [92]. Vorinostat can sensitize HCC cells to sorafenib treatment by regulating the acetylation level of Beclin1.…”

Lysine Acetyltransferase GCN5 Potentiates the Growth of Non-small Cell Lung Cancer via Promotion of E2F1, Cyclin D1, and Cyclin E1 Expression

“…Hypoacetylation of a specific set of genes results from an imbalance between KATs and HDACs and is associated with the transformed state of cancer cells (3)(4)(5)(6). HDAC inhibitors, which can suppress HDAC enzymatic activity and reactivate epigenetically silenced antitumor genes, represent useful tools for cancer prevention and therapy (7). Currently, clinical trials employing HDAC inhibitors have been hampered by their lack of specificity.…”

“…Currently, clinical trials employing HDAC inhibitors have been hampered by their lack of specificity. Most HDAC inhibitors target a panel of HDAC superfamily members, and individual HDAC members regulate diverse cellular pathways (7,8). Therefore, the inhibition of HDAC enzymatic activity using HDAC inhibitors often results in unintentional gene activation and the development of drug resistance (9,10).…”