HDAC INHIBITORS AGAINST CANCERS

by Selleckchem | Aug 01 2012

EPIGENETIC MODULATION VIA HDAC INHIBITION:
Histones acetylation is vital process in the functions like cellular growth and cell death by inhibiting the transcription of proteins which is caused by the removal of acetyl groups from histones as a result the DNA binding increases and DNA is condensed. When this process is disturbed it leads to uncontrolled growth of cells leading to the formation of cancers and also neurodegenerative diseases. HDAC inhibition for the treatment of cancer comes by the use of HDAC inhibitors. Successful studies elucidating mechanisms of HDAC inhibitors led to their vast applications in different clinical and preclinical studies [1]. HDAC levels can be assessed by using various assays developed for this purpose [2]. These assays can be performed in lab by the help of kits. Researchers can perform microplate reader compatible and nonisotopic HDAC inhibitor assay and one for compound profiling and robotic screening [4] and in addition to this simply a flourogenic assay can be performed for high-throughput screening [5].

FAMOUS HDAC INHIBITORS:
Long time ago link between cancer and tumor formation was reported which lead to the concept of selective HDAC inhibitors, potential approach for cancer therapy [6]. There is huge number of HDAC inhibitors and some of the most famous are enlisted: CUDC101, Entinostat, Panobinostat or SAHA, Romidepsin and Belinostat. For research purposes one can easily access to these inhibitors by contacting to the respective suppliers. These inhibitors are also used for the mood stabilization and anti-epileptics for those patients which are suffering from various neurological and psychiatric problems. Many of these antagonist molecules are in developing stages and some of them are also being used in clinics. HDAC-2 inhibitors are also implicated for neurodegenerative diseases in addition to cancer treatment [7].

CLINICAL STUDIES OF HDAC INHIBITORS:
T-cell lymphoma patients were administered with Panobinostat during clinical phase I-II and good results were obtained [8]. Belinostat was noted to be potent against advanced malignant pleural mesothelioma during clinical phase II studies [9] and this inhibitor has little side effects and stabilizing disease in patients. CUDC-101 that is a multi kinase inhibitor also showed efficient results by affecting EGFR, HDAC and HER2 which ultimately leads to the inhibition of cancerous growth [10]. One more HDAC inhibitor that is undergoing clinical trials is Valproate which acted as a potent agent against tumor cells and induced apoptosis in cancer of cervix during clinical trial phase. One of the leading inhibitor is Vorinostat which gained the very first approval from FDA or Food and Drug Administration. Entinostat is currently in phase II of clinical trials on Hodgkin’s lymphoma and in metastatic lung cancer and patients of breast cancer.

REFERENCES:
1. Iglesias OM, e.a., Histone deacetylase inhibitors: mechanism of action and therapeutic use in cancer. Clinical and Translational Oncology, 2008.
2. Yuan Z, e.a., Histone Deacetylase Activity Assay Methods in Molecular Biology, 2009.
3. Heltweg B, J.M., A Microplate Reader-Based Nonisotopic Histone Deacetylase Activity Assay. Analytical Biochemistry, 2002.
4. Ciossek T, e.a., A homogeneous cellular histone deacetylase assay suitable for compound profiling and robotic screening. Analytical Biochemistry, 2008.
5. Wegener D, e.a., A fluorogenic histone deacetylase assay well suited for high-throughput activity screening. Chem Biol., 2003.
6. Richon VM, a.O.B.J., Histone Deacetylase Inhibitors: A New Class of Potential Therapeutic Agents for Cancer Treatment. Clin. Cancer Res, 2002.
7. Chuang DM, e.a., Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends in Neurosciences, 2009.
8. Prince HM, B.M., Panobinostat (LBH589): a novel pan-deacetylase inhibitor with activity in T cell lymphoma. Hematology Meeting Reports, 2009.
9. Ramalingam SS, e.a., Phase II study of belinostat (PXD101), a histone deacetylase inhibitor, for second line therapy of advanced malignant pleural mesothelioma. J Thorac Oncol., 2009.
10. Lai CJ, e.a., CUDC-101, a Multitargeted Inhibitor of Histone Deacetylase, Epidermal Growth Factor Receptor, and Human Epidermal Growth Factor Receptor 2, Exerts Potent Anticancer Activity. Cancer Res, 2010.
11. Blanco AC, e.a., Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study. Molecular Cancer, 2005.

Cat.No.	Product Name	Information
S1194	CUDC-101	CUDC-101 is a potent multi-targeted inhibitor against HDAC, EGFR and HER2 with IC50 of 4.4 nM, 2.4 nM, and 15.7 nM, and inhibits class I/II HDACs, but not class III, Sir-type HDACs. Phase 1.
S1053	Entinostat (MS-275)	Entinostat (MS-275, SNDX-275) strongly inhibits HDAC1 and HDAC3 with IC50 of 0.51 μM and 1.7 μM in cell-free assays, compared with HDACs 4, 6, 8, and 10. Entinostat induces autophagy and apoptosis. Phase 3.
S1030	Panobinostat (LBH589)	Panobinostat (LBH589, NVP-LBH589) is a novel broad-spectrum HDAC inhibitor with IC50 of 5 nM in a cell-free assay. Panobinostat (LBH589) induces autophagy and apoptosis. Panobinostat effectively disrupts HIV latency in vivo. Phase 3.
S1047	Vorinostat (SAHA)	Vorinostat (SAHA) is an HDAC inhibitor with IC50 of ~10 nM in a cell-free assay. Vorinostat abrogates productive HPV-18 DNA amplification.
S1085	Belinostat	Belinostat is a novel HDAC inhibitor with IC50 of 27 nM in a cell-free assay, with activity demonstrated in cisplatin-resistant tumors. Belinostat (PXD101) induces autophagy.