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HISTONE DEACETYLASE INHIBITORS BEYOND CANCER TREATMENT

EPIGENEITIC MODULATION AND HDAC INHIBITORS
In cellular genome a major part comprises of histone proteins and these proteins upon addition of acetyle group perform some of the most important cellular pathways are controlled by these proteins, these pathways include cell growth and proliferation and programmed cell death. When the acetyle group is detached from histones the process of apoptosis starts because most of the genetic expression of some vital proteins is ceased due to deacetylation and in addition to this the DNA condensation is also increased due to increased DNA binding capacity. It has been noticed that during neurodegenerative diseases the process of deacetylation is disturbed which leads to different types of cancers and tumors which is characterized by uncontrolled cell proliferation. These studies encouraged the discoveries of HDAC inhibitors and also enlighten the HDAC inhibition process. In preclinical and clinical evaluations HDAC inhibitions have been applied which leads to the successful and detailed use of this process by good number of researchers [1].  Various activity assays are available for the estimation of HDACs levels [2]. Kits are available for such assays however these can also be performed manually in the lab. HDAC inhibitors analysis can also be done by a nonisotopic assay which is microplate reader compatible [3] and test for robotic screening and compound profiling is also available [4] or another assay which is suitable for high throughput screening [5].


FAMOUS HDAC INHIBITORS:
HDAC inhibitors were come into existence many years ago when relation between tumorigenesis and cancers was established with HDAC; these agents were proved as forceful drugs against treatment of tumors and cancer [6]. Various famous inhibitors including Entinostat, Vorinostat or SAHA, Belinostat, Romidepsin, Panobinostat (LBH589) and CUDC-101 are potent HDAC inhibitors. These inhibitors can be easily purchased from any of the HDAC inhibitors supplier. In addition to treatment of cancer HDAC inhibitors are also used for the mood stabilization of psychiatric and neurologic patients and beyond this these are also used as anti-epileptics. As these molecules are diversely found, some of the HDAC antagonist molecules are still under different stages of development and many of these compounds are being used in clinics. Small molecule HDAC inhibitors are effectively used for different types of cancers and these are also applied in neurodegenerative disorders [7].


HISTONE DEACETYLASE INHIBITORS UNDER CLINICAL STUDIES:
During clinical evaluation phase I and II the effect of T-cell lymphoma patients were treated with Panobinostat and the results reported were strongly in favor of this drug [8]. And in advanced and malignant pleural mesothelioma the efficiency of Belinostat was evaluated which ultimately proved as an effective drug treatment [9] although with little side effects but in a diseases stabilization manner. On the other hand CUDC-101 is a multi kinase inhibitor having such properties which affect the following EGFR, HER2 and HDACs and reported as effective against cancer [10]. During clinical phase I the patients of cervical cancer were treated with Valproate and it was proved as powerful HDAC inhibitor which is characterized by the apoptosis and checking of cellular growth [11]. But among all the HDAC inhibitors the first FDA approved inhibitor is Vorinostat and used for the treatment of CTCL. Another inhibitor with similar properties is being evaluated under clinical phase II trials which is used against advanced breast cancer patients, Hodgkin’s lymphoma and metastatic lung cancer and is under process.


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.
 

Related Products

Cat.No. Product Name Information Publications Customer Product Validation
S1053 Entinostat (MS-275) Entinostat (MS-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. (296) (14)
S1047 Vorinostat (SAHA) Vorinostat (suberoylanilide hydroxamic acid, SAHA) is an HDAC inhibitor with IC50 of ~10 nM in a cell-free assay. Vorinostat abrogates productive HPV-18 DNA amplification. (315) (20)
S1085 Belinostat (PXD101) Belinostat (PXD101) 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. (59) (8)
S3020 Romidepsin (FK228, Depsipeptide) Romidepsin (FK228, depsipeptide) is a potent HDAC1 and HDAC2 inhibitor with IC50 of 36 nM and 47 nM in cell-free assays, respectively. Romidepsin (FK228/depsipeptide) controls growth and induces apoptosis in neuroblastoma tumor cells. (115) (6)
S1030 Panobinostat (LBH589) Panobinostat (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. (240) (12)
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. (12) (3)

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