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HISTONE DEACETYLASE INHIBITORS – CANCERS AND BEYOND

HDAC INHIBITIORS AND EPIGENEITIC MODULATION:
Histone proteins are major part of cellular genome and acetylation of these proteins plays a mile stone role in some of the most important cellular mechanisms such as growth of cell and cell death by apoptosis. The process which controls apoptosis process is carried out by checking the gene transcription of different important proteins by removing acetyl groups from histones, this deacetylation leads to condensation of DNA due to increasing capacity of DNA binding. In neurodegenerative diseases this mechanism of deacetylation goes wrong leading to various types of cancers in which cell proliferation is uncontrolled. This problem leads to the HDAC inhibitor pathway and smoothes the process of HDAC inhibition. HDAC inhibitions have been employed in preclinical and clinical studies due to which extensive and successful use of this process is targeted by many researchers [1]. HDACs levels estimation has been developed by different activity assays [2]. These assays are carried out by manually in the research lab or by kit methods. A nonisotopic assay that is microplate reader compatible can also be performed by researchers for the analysis of HDAC inhibitors [3], an appropriate test for compound profiling and robotic screening [4] or a suitable fluorescence assay for high-throughput screening [5]. 


RENOWNED HDAC INHIBITORS:
Many years ago the relation between HDAC and tumorigenesis or cancers was established due to which various selective HDAC inhibitors came to light, these compounds were proved as potential therapeutic agents for the treatment of tumors [6]. Among many of these inhibitors SAHA or Vorinostat, Entinostat, Belinostat, Panobinostat, Romidepsin, LBH589 and CUDC-101 are included. For the purpose of research one can buy these HDAC inhibitors from any of the HDACi supplier. Beyond the cancer treatment HDACi are also used for the mood stabilization of neurologic and psychiatric related patients and one another application of these inhibitors is found as anti-epileptics. Due to high diversity of these molecules some of the HDAC antagonist molecules are in various stages of development and many of these molecules are efficiently used in clinics. Against various types of cancers small molecule HDAC inhibitors are being used as these molecules have well anti tumor activity and these molecules are also used in neurodegenerative diseases [7].
 

CLINICAL TRIALS OF HISTONE DEACETYLASE INHIBITORS:
During clinical trials phase I and II Panobinostat was used and it was noted that this drug is valuable against T-cell lymphoma patients [8]. Similarly Belinostat was found as very efficient in clinical phase II studies on patients with advanced malignant pleural mesothelioma [9] proving its ability of disease stabilization and with little side effects. CUD-101 is another such inhibitor which is with multi kinase inhibitor properties and targets following HER2, EGFR and HDACs, this agent also reported as potent against cancer cells [10]. In studies of cervical cancer patients during clinical trials phase I, Valproate was found as powerful HDAC inhibitor as it has the ability to inhibit the growth of cancer cells and it also induces apoptosis [11]. However Vorinostat is the first FDA approved HDAC inhibitor for the treatment of CTCL. One more such inhibitor is under clinical phase II evaluation where Hodgkin’s lymphoma patients, advanced breast cancer patients and patients with metastatic lung cancer are under process for treatment.
 

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
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. (17) (3)
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. (373) (14)
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. (327) (12)
S1085 Belinostat (PXD101) Belinostat (PXD101, NSC726630, PX-105684) 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. (81) (8)

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