Entinostat performs almost similar functions as Belinostat and Panobinostat
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Posted On :
Jan-09-2012
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Article Word Count :
787
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Entinostat, is also known with different other names such as MS-275, SNDX-275 and MS-27-275. This compound is among HDAC inhibitors and is selective for HDAC1 and HDAC3. It performs almost similar functions as Belinostat and Panobinostat which are HDAC inhibitors. In human beings under in vivo conditions Entinostat is known to show a great anti tumor activity.
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INTRODUCTION
Entinostat, is also known with different other names such as MS-275, SNDX-275 and MS-27-275. This compound is among HDAC inhibitors and is selective for HDAC1 and HDAC3. It performs almost similar functions as Belinostat and Panobinostat which are HDAC inhibitors. In human beings under in vivo conditions Entinostat is known to show a great anti tumor activity. It shows effects of different ranges in cancerous cells depending upon the quantity of induction. This compound is currently under phase I clinical trials.
Nuclear region of tumor cell lines contain histones and Entinostat is found to have a great potency of hyperacetylation of these histones. Entinostat is synthetic banzamide derivative, has a chemical name N-(2-aminophenyl)-4-[N-(pyridin-3-yl methoxycarbonyl) aminomethyl] benzamide [1]. In case of leukemia, growth of tumor cell lines is arrested by the stimulation of this derivative. There is a copy mutation of the tandem genes such as FLT3-ITD gene internally in these cell lines of leukemia. When inhibited by Entinostat, there is a reduced level of the l phosohorylated and total FLT3. As a result an Akt-ERK-STAT5 mediated downstream deactivation of signaling pathway occurs. Acetylation of HSP90 is also a response of its induction [2].
An actin binding protein called gelsolin and another protein named p21WAF1/CIP1are both responsible of tumor suppression. After 48 hours of stimulation by Entinostat, intra-cellular levels of these proteins in cells are reported to be highly increased.P53 stimulates the p21WAF1/CIP1 causing the decrease levels of cyclin dependent kinases. There is no effect of Entinostat on the expression of P53 gene. Acetylation process of the histone proteins is actually the basic mechanism behind the stimulation process and this also leads to the cell death [1].
At all concentrations Entinostat found to induce the acetylation of H3 and H4histones. It had anti-proliferative effect upon induction of 1μm and the growth of cancer cells (U937) is arrested. The cell cycle was arrested in the G0-G1phase due to very low concentration of Entinostat. When used in different combinations it has been shown that there are no toxic effects of this molecule. However this compound can also be used with DNA transferases.
When induced in higher concentration up to 5μm, it causes cell death by stimulating the apoptotic pathway. On this concentration p27KIP1, p21CIP1/WAF1, and pRB are degraded promoting apoptosis [3]. Stimulation of apoptosis is a receptor independent process. Mitochondrial injury occurs due to the breakdown of p21CIP1/WAF1 causing mitochondrial dysfunction leading to apoptosis [5]. After the screening of chemical libraries the scientists discovered that the entinostat has also the ability to pass through the blood brain barrier (barrier in brain and blood). So this is also a unique property of this compound.
Silencing of tumor suppressor genes occurs in case of lung cancer cell lines and also found in some other forms of cancers and tumors as well. Entinostat combines with DNA methyl transferases and causes the expression of these genes which are epigenetically silenced [4]. The re-expression of these important genes along with the drug act more strongly on the tumor and cancer cells. In this way reinforcing the effect of each other the cancer cell death occurs.
CONCLUSION
Entinostat, an effective HDAC inhibitor controls the growth of cancerous cell lines showing various kinds of effects depending upon different concentrations of induction. It causes mitochondrial injury leading to apoptosis. Expression of different tumor suppressor genes is also checked by Entinostat. This is another leading inhibitor of the HDAC family and promising to treat cancers and the tumors either alone or in combination to different DNA transferases.
REFERENCES
1. Saito A, Yamashita T, et al. A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in
vivo antitumor activity against human tumors. PNAS 1999 April 13; 96(8): 4592-4597.
2. Nishioka C, Ikezoe T, et al. MS-275, a novel histone deacetylase inhibitor with selectivity against
HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in
AML cells. Leuk Res 2008 Sep; 32(9):1382-92.
3. Gervais JLM, Seth P and Zhang H. Cleavage of CDK Inhibitor p21Cip1/Waf1 by Caspases Is an Early
Event during DNA Damage-induced Apoptosis. The Journal of Biological Chemistry 1998 July 24; 273:
19207-19212.
4. Juergens RA, Vendetti F, et al. Phase I trial of 5-azacitidine (5AC) and SNDX-275 in advanced lung
cancer (NSCLC). J Clin Oncol 26; 2008 (May 20 suppl; abstr 19036).
5. Rosato RR, Almenara JA, and Grant S. The Histone Deacetylase Inhibitor MS-275 Promotes
Differentiation or Apoptosis in Human Leukemia Cells through a Process Regulated by Generation of
Reactive Oxygen Species and Induction of p21CIP1/WAF1 1. Cancer Res 2003 July 1; 63: 3637.
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