HDAC INHIBITORS AGAINST TOMORS

by Selleckchem | Aug 22 2012

HDAC INHIBITION: A SOURCE OF EPIGENETIC MODULATION
Histone acetylation is an essential process in functions like cell growth and cellular death by causing the inhibition of transcription of proteins caused by removal of the acetyl groups from the histone proteins, as a result of which the binding of DNA is increased, causing it to be condensed. A disturbance in this phenomenon leads to an uncontrolled growth of the cells that leads to the production of tumors and neurodegenerative diseases as well. HDAC inhibition is performed to treat various forms of tumors by using HDAC-2 inhibitors. Different successful studies at various levels have elucidated the mechanism of action of HDAC inhibitors leading to their enormous applications in various preclinical and clinical trials [1]. The levels of HDAC inhibitors can be assessed by the use of different sort of assays specially developed for this reason [2]. These chemical assays can be performed in laboratory by using various kits. The researchers can perform nonisotopic HDAC inhibitor and microplate reader compatible assay and the one for the robotic screening [4] and compound profiling. In addition to it a simple flourogenic assay can also be used for the high-throughput screening process [5].

RENOWNED HDAC INHIBITORS:
A long time ago the link between tumor and cancer formation was elucidated that led to the thought of the selective HDAC inhibitors as a potential approach for the therapy of cancer [6]. There is an enormous number molecules of HDAC inhibitors from which some most well-known are enlisted below: Entinostat, SAHA or Panobinostat, CUDC101, Belinostat and Romidepsin. For the research reasons a person can easily access to these inhibiting drugs by contacting their respective suppliers. HDAC inhibitors are also being used for mood stabilization and as anti-epileptics for the patients suffering from different types of psychiatric and neurological problems. Among these antagonist molecules a lot of molecules are now at developing stages and some molecules are being used in the clinics. In addition to the treatment of cancer, some HDAC-6 inhibitors are also caught up for the treatment of neurodegenerative diseases [7].

HDAC INHIBITORS: CLINICAL STUDIES
In clinical trials phase I and phase II, Panobinostat was used for treatment of the patients of T-cell lymphoma and it showed very good results [8]. In clinical trials phase II, Belinostat was also observed to be very potent against the advanced malignant pleural mesothelioma [9] showing very slight side effects and disease stabilization in the patients. A multi bayer kinase inhibitor named CUDC-101 has also shown remarkable results by causing its effects on HDAC, HER2 and EGFR leading to the inhibition of cancer growth [10]. Valproate is another eminent HDAC inhibitor undergoing the clinical studies and observed to be a potent chemical agent against the tumor cells growth and it also stimulated apoptosis in cervical cancer during its clinical trials. The most leading HDAC inhibitor is Vorinostat that has gained the first approval from Food and Drug Administration or FDA. For the treatment of metastatic lung cancer, breast cancer and Hodgkin’s lymphoma, Entinostat is currently under the clinical trials phase II.

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
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.
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.
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.
S3020	Romidepsin	Romidepsin (FK228, Depsipeptide, FR 901228, NSC 630176) 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.