Synergistic Anticancer Effect of Glycolysis and Histone Deacetylases Inhibitors in a Glioblastoma Model

Over the last decade, we have seen tremendous progress in research on 2-deoxy-D-glucose (2-DG) and its analogs. Clinical trials of 2-DG have demonstrated the challenges of using 2-DG as a monotherapy, due to its poor drug-like characteristics, leading researchers to focus on improving its bioavailability to tissue and organs. Novel 2-DG analogs such as WP1122 and others have revived the old concept of glycolysis inhibition as an effective anticancer strategy. Combined with other potent cytotoxic agents, inhibitors of glycolysis could synergistically eliminate cancer cells. We focused our efforts on the development of new combinations of anticancer agents coupled with 2-DG and its derivatives, targeting glioblastoma, which is in desperate need of novel approaches and therapeutic options and is particularly suited to glycolysis inhibition, due to its reliance on aerobic glycolysis. Herein, we present evidence that a combined treatment of 2-DG analogs and modulation of histone deacetylases (HDAC) activity via HDAC inhibitors (sodium butyrate and sodium valproate) exerts synergistic cytotoxic effects in glioblastoma U-87 and U-251 cells and represents a promising therapeutic strategy.

Histone Deacetylases and Their Isoform-Specific Inhibitors in Ischemic Stroke

Cerebral ischemia is the second leading cause of death in the world and multimodal stroke therapy is needed. The ischemic stroke generally reduces the gene expression due to suppression of acetylation of histones H3 and H4. Histone deacetylases inhibitors have been shown to be effective in protecting the brain from ischemic damage. Histone deacetylases inhibitors induce neurogenesis and angiogenesis in damaged brain areas promoting functional recovery after cerebral ischemia. However, the role of different histone deacetylases isoforms in the survival and death of brain cells after stroke is still controversial. This review aims to analyze the data on the neuroprotective activity of nonspecific and selective histone deacetylase inhibitors in ischemic stroke.

Co-treatment of Garlic-Oils Extract, Dially-thiosulphate, and Histone Deacetylases Inhibitors (HDACI) Synergistically Inhibited Cell Proliferation and induced Apoptosis in Hepatocellular carcinoma cell lines

Introduction/Objective Hepatocellular carcinoma (HCC) is the most common cause of cancer-deaths worldwide. Garlic (Allium Sativum), is a natural-medicinal herb which has anti-fungal, anti-bacterial, anti-inflammatory, anti-virus, and antiproliferative activities. Garlic-oil soluble-sulfur-compounds, diallyl-thiosulphate, (DT) are more effective than water-soluble-compounds in protection against cancer due to its capacity to induce apoptosis and revise anti- multidrug-resistance. Histone deacetylases inhibitors (HDACIs) are inhibitors of anti-cancer agents that play a role in inducing death, differentiation, apoptosis induction, and cell-cycle arrest in different cancer-types. The present studying aims to investigate the anti-proliferative effect of organosulfur-oil DT extract of garlic by possible modulation of HDACIs role on HCC cell-lines. Methods/Case Report Two HDACIs, suberanilohydroxamic acid (SAHA) and trichostatinA (TSA), were used to investigate their role on proliferation of two HCC cell-lines, HepG2 and Hep3B, respectively. Cell proliferation was examined by Wst-1 assay, apoptosis induction signaling pathways, cell-cycle analysis, and western-blot analysis of the major oncogenic signaling pathways in the two tested cell-lines. Results (if a Case Study enter NA) Our data showed that DT significantly inhibited the cell-proliferation and induced cell-cycle arrest at G2/M phase in both HCC cell-lines. In addition, co-treatment of DT and HDACIs for 48h enhanced the cell inhibitory effect and induced apoptosis by up-regulation of p53, p21, and Bax protein expression and down- regulation of Bcl-2 and cyclin-D1 protein expression compared to control or each treatment alone. Furthermore, the data showed that DT significantly increased caspases-3 activity in Hep-G2 cell-line than that of Hep3B cell-line in a dose dependent-time compared to the control. Apoptosis induction was consistent with up-regulated caspase-3 activity, and HepG2 cells, but not Hep3B cells, showed a significant increase in response to co-treatment of DT with SAHA compared to co-treatment with TSA. Conclusion The data of the present study demonstrated that DT, non-toxicity compound, might be a new modulator for HDACIs effects, which in turn might be a promising prospective agent for HCC treatment.

Expression of Adenoviral E1A in Transformed Cells as an Additional Factor of HDACi-Dependent FoxO Regulation

The adenoviral early region 1A (E1A) protein has proapoptotic and angiogenic activity, along with its chemosensitizing effect, making it the focus of increased interest in the context of cancer therapy. It was previously shown that E1A-induced chemosensitization to different drugs, including histone deacetylases inhibitors (HDACi), appears to be mediated by Forkhead box O (FoxO) transcription factors. In this study, we explore the relationship between E1A expression and the modulation of FoxO activity with HDACi sodium butyrate (NaBut). We show here that the basal FoxO level is elevated in E1A-expressing cells. Prolonged NaBut treatment leads to the inhibition of the FoxO expression and activity in E1A-expressing cells. However, in E1A-negative cells, NaBut promotes the transactivation ability of FoxO over time. A more detailed investigation revealed that the NaBut-induced decrease of FoxO activity in E1A-expressing cells is due to the NaBut-dependent decrease in E1A expression. Therefore, NaBut-induced inhibition of FoxO in E1A-positive cells can be overcome under unregulated overexpression of E1A. Remarkably, the CBP/p300-binding domain of E1Aad5 is responsible for stabilization of the FoxO protein. Collectively, these data show that the expression of E1A increases the FoxO stability but makes the FoxO level more sensitive to HDACi treatment.

Histone Deacetylase Inhibitors As Potential Therapeutic Agents For Various Disorders

Epigenetic modification acetylation or deacetylation of histone considered as an important element in various disorders. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are the enzymes which catalyse the acetylation and deacetylation of histone respectively. It helps in regulating the condensation of chromatin and transcription of genes. Lysine acetylation and deacetylation present on the nucleosomal array of histone is the key factor for gene expression and regulation in a normal working living cell. Modification in histone protein will lead to the development of cancer and can cause various neurodegenerative disorders. To safeguard the cells or histone proteins from these diseases histone deacetylase inhibitors are used. In this review, the main focus is upon the role of histone deacetylases inhibitors in various diseases.