LAQ824 targets regulators of cell cycle and growth

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LAQ824 targets regulators of cell cycle and growth

Posted On : Jan-10-2012 | seen (723) times | Article Word Count : 808 |

HDAC inhibitors have great potential to destroy tumor and cancer cells. LAQ824 is one of HDAC inhibitors as different animal xenografts had depicted the role of this compound during various experiments. The mechanism of action is similar as in other such inhibitors. The LAQ824 arrest the growth of cell by cell cycle arrest or inducing apoptosis.

INTRODUCTION
HDAC inhibitors have great potential to destroy tumor and cancer cells. LAQ824 is one of HDAC inhibitors as different animal xenografts had depicted the role of this compound during various experiments. The mechanism of action is similar as in other such inhibitors. The LAQ824 arrest the growth of cell by cell cycle arrest or inducing apoptosis.

CHEMICAL PROPERTIES OF LAQ824
Like other different compounds LAQ824 is a synthetic chemical and derivative of hydroxamic acid and chemically it is also known as cinnamic acid [1]. The low concentration of LAQ824 are effective even nanomolar concentrations [2]. Like belinostat the LAQ824 is also in clinical evaluation and is currently in clinical phase I. LAQ824 targets H3 (histone) and affects it acetylation process efficiently. It also involved in the depletion of certain proteins specifically cyclin dependent kinase 2 which is linked with the high expression of heat shock protein (Hsp 72), proving LAQ824 effect on hsp90 chaperon functions. This compound also effects CRAF protein [2]. The acetylation of the Hsp90 thought to be the cause of certain conformational changes thereby inhibiting its proper function [2].
ROLE OF LAQ824 WITH CRA
HMV-I and A2058 cancer cell lines were subjected to CRA which is 13-cis-retinoic acid, it is reported that there was no effect on these cell lines. However when the combination of CRA and LAQ824 was used up to 98% effect was noticed to inhibit the cell lines growth. Generally HDACs inhibitors act on the cancer suppressor genes resulting in the death of cell for example entinostat and pyroxamide target special tumor suppressor genes. Retinoic acid receptor β (RARβ) epigenetic repression is reverted by these inhibitors. The gene expression of RARβ is decreased due to the high methylation of genes especially at promoter region and acetylation of histones. LAQ824 has the ability to reverse the RARβ2 epigenetic silencing. By the given mechanism it reactivated the sensitivity of retinoid [4].
LAQ824: AN APOPTOSIS INDUCER
Like other apoptosis inhibitors LAQ824 either checked the G2 stage of cell cycle or stimulated the apoptosis in cancer cell lines (HMV-I and A2058 melanoma cell lines). But the degree of apoptosis induction was variable in various cell lines. The basic mechanism of action is found to be the production of free radicals for example peroxides and oxygen ions in these melanoma cell lines. In HMV-I cancer cell lines the SM22 expression was also noticed due to induction by LAQ824. The tumor cell death was observed as due to the lethal effect of both LAQ824 and CRA [4]. The effect of LAQ824 isnot only limited to tumor cells but also to normal cells as they were noticed as arrested in G2-M phase, these results were analyzed by flow cytometry. However an enhanced level of sub-G1was also observed in cancer ell lines [3]. The results revealed that the effect of LAQ824 is on the tumor or cancer cell lines but not as much in normal cell lines. The LAQ824 effects both of H3 and H4 by their enhanced acetylation [3].
LAQ824: ACTION ON P21GENE
Among various genes the cell cycle is regulated by p21 gene. LAQ824 enhances the genetic expression of p21 [1] [5]. Certain substrate like Rb is hypophosphorylated by the high gene expression of p21. The Rb serves as substrate of kinase (cyclin-dependent kinase). Therefore high expression genetic of p21 is connected with inhibited activity of kinase. The hypophosphorylation of Rb results in the cell cycle arrest at G1 phase. The whole mechanism shows the indirect of LAQ824 in the process of apoptosis.
CONCLUSION
In summary LAQ824 initiate apoptosis by arresting cell cycle and also targets some other regulators of cell cycle and growth. LAQ824 produces free radicals in cellular environment. It is specific for tumor cells. The LAQ824 is currently in clinical trials and promising in future against cancer.

REFERENCES
1. Catley L, Weisberg E, et al. NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. Blood 2003 Oct 1; 102(7):2615-22.
2. Bono JSD, Kristeleit R, et al. Phase I Pharmacokinetic and Pharmacodynamic Study of LAQ824, a Hydroxamate Histone Deacetylase Inhibitor with a Heat Shock Protein-90 Inhibitory Profile, in Patients with Advanced Solid Tumors. Clin Cancer Res 2008 Oct 15; 14: 6663.
3. Atadja P, Gao L, et al. Selective Growth Inhibition of Tumor Cells by a Novel Histone Deacetylase Inhibitor, NVP-LAQ824. Cancer Res 2004 Jan 15; 64: 689.
4. Kato Y, Salumbides BC, et al. Antitumor effect of the histone deacetylase inhibitor LAQ824 in combination with 13-cis-retinoic acid in human malignant melanoma. Mol Cancer Ther 2007 Jan; 6(1):70-81.
5. Atadja P, Hsu M, et al. Molecular and cellular basis for the anti-proliferative effects of the HDAC inhibitor LAQ824. Novartis Found Symp 2004; 259:249-66; discussion 266-8, 285-8.
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<h1>LAQ824 targets regulators of cell cycle and growth</h1> Author: <a href='http://www.articleseen.com/profile_Dr.Rabia.aspx'>Dr.Rabia</a> INTRODUCTION
HDAC inhibitors have great potential to destroy tumor and cancer cells. LAQ824 is one of HDAC inhibitors as different animal xenografts had depicted the role of this compound during various experiments. The mechanism of action is similar as in other such inhibitors. The LAQ824 arrest the growth of cell by cell cycle arrest or inducing apoptosis. 
 
CHEMICAL PROPERTIES OF LAQ824
Like other different compounds LAQ824 is a synthetic chemical and derivative of hydroxamic acid and chemically it is also known as cinnamic acid [1]. The low concentration of LAQ824 are effective even nanomolar concentrations [2]. Like belinostat the LAQ824 is also in clinical evaluation and is currently in clinical phase I. LAQ824 targets H3 (histone) and affects it acetylation process efficiently. It also involved in the depletion of certain proteins specifically cyclin dependent kinase 2 which is linked with the high expression of heat shock protein (Hsp 72), proving LAQ824 effect on hsp90 chaperon functions. This compound also effects CRAF protein [2]. The acetylation of the Hsp90 thought to be the cause of certain conformational changes thereby inhibiting its proper function [2].
ROLE OF LAQ824 WITH CRA
HMV-I and A2058 cancer cell lines were subjected to CRA which is 13-cis-retinoic acid, it is reported that there was no effect on these cell lines. However when the combination of CRA and LAQ824 was used up to 98% effect was noticed to inhibit the cell lines growth. Generally HDACs inhibitors act on the cancer suppressor genes resulting in the death of cell for example entinostat and pyroxamide target special tumor suppressor genes. Retinoic acid receptor β (RARβ) epigenetic repression is reverted by these inhibitors. The gene expression of RARβ is decreased due to the high methylation of genes especially at promoter region and acetylation of histones. LAQ824 has the ability to reverse the RARβ2 epigenetic silencing. By the given mechanism it reactivated the sensitivity of retinoid [4].
LAQ824: AN APOPTOSIS INDUCER
Like other apoptosis inhibitors LAQ824 either checked the G2 stage of cell cycle or stimulated the apoptosis in cancer cell lines (HMV-I and A2058 melanoma cell lines). But the degree of apoptosis induction was variable in various cell lines. The basic mechanism of action is found to be the production of free radicals for example peroxides and oxygen ions in these melanoma cell lines. In HMV-I cancer cell lines the SM22 expression was also noticed due to induction by LAQ824. The tumor cell death was observed as due to the lethal effect of both LAQ824 and CRA [4]. The effect of LAQ824 isnot only limited to tumor cells but also to normal cells as they were noticed as arrested in G2-M phase, these results were analyzed by flow cytometry. However an enhanced level of sub-G1was also observed in cancer ell lines [3]. The results revealed that the effect of LAQ824 is on the tumor or cancer cell lines but not as much in normal cell lines. The LAQ824 effects both of H3 and H4 by their enhanced acetylation [3].
LAQ824: ACTION ON P21GENE
Among various genes the cell cycle is regulated by p21 gene. LAQ824 enhances the genetic expression of p21 [1] [5]. Certain substrate like Rb is hypophosphorylated by the high gene expression of p21. The Rb serves as substrate of kinase (cyclin-dependent kinase). Therefore high expression genetic of p21 is connected with inhibited activity of kinase. The hypophosphorylation of Rb results in the cell cycle arrest at G1 phase. The whole mechanism shows the indirect of LAQ824 in the process of apoptosis.
CONCLUSION
In summary LAQ824 initiate apoptosis by arresting cell cycle and also targets some other regulators of cell cycle and growth. LAQ824 produces free radicals in cellular environment. It is specific for tumor cells. The LAQ824 is currently in clinical trials and promising in future against cancer.
 
REFERENCES
1. Catley L, Weisberg E, et al. NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. Blood 2003 Oct 1; 102(7):2615-22.
2. Bono JSD, Kristeleit R, et al. Phase I Pharmacokinetic and Pharmacodynamic Study of LAQ824, a Hydroxamate Histone Deacetylase Inhibitor with a Heat Shock Protein-90 Inhibitory Profile, in Patients with Advanced Solid Tumors. Clin Cancer Res 2008 Oct 15; 14: 6663.
3. Atadja P, Gao L, et al. Selective Growth Inhibition of Tumor Cells by a Novel Histone Deacetylase Inhibitor, NVP-LAQ824. Cancer Res 2004 Jan 15; 64: 689.
4. Kato Y, Salumbides BC, et al. Antitumor effect of the histone deacetylase inhibitor LAQ824 in combination with 13-cis-retinoic acid in human malignant melanoma. Mol Cancer Ther 2007 Jan; 6(1):70-81.
5. Atadja P, Hsu M, et al. Molecular and cellular basis for the anti-proliferative effects of the HDAC inhibitor LAQ824. Novartis Found Symp 2004; 259:249-66; discussion 266-8, 285-8.
Related Posts:
JNJ-26481585 – A COMPOUND WITH BROAD SPECTRUM EFFECTS
ITF2357 (GIVINOSTAT) – A POTENT APOPTOSIS INDUCERAbout the Author: We pays great attention to the purity, stability and activity of the products like <a rel="nofollow" href="http://www.selleckchem.com/products/MS-275.html">Entinostat</a>, <a rel="nofollow" href="http://www.selleckchem.com/products/SRT1720.html">SRT1720</a>, <a rel="nofollow" href="http://www.selleckchem.com/products/Y-27632.html">Y-27632</a> & more. Article Source: <a href='http://www.articleseen.com/Article_LAQ824-targets-regulators-of-cell-cycle-and-growth_131302.aspx'> http://www.articleseen.com/Article_LAQ824 targets regulators of cell cycle and growth_131302.aspx</a>

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