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AR-42 (HDAC-42) in the inhibition of various cancer cells
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Posted On :
Jan-04-2012
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Article Word Count :
831
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AR-42 is a new histone deacetylase inhibitor like vorinostat which regulates apoptosis via different pathways. It affects different cell cycle stages leading to the inhibition of cell proliferation in an effective manner. Proteins like tubulin and histones are also affected by this inhibitor.
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INTRODUCTION
AR-42 is a new histone deacetylase inhibitor like vorinostat which regulates apoptosis via different pathways. It affects different cell cycle stages leading to the inhibition of cell proliferation in an effective manner. Proteins like tubulin and histones are also affected by this inhibitor.
CHEMICAL NATURE AND MECHANISM OF ACTION
AR-42 was also named as OSU-HDAC42. It is an inhibitor of histone deacetylase and hydroxamate-tethered phenylbutyrate derivative; it promotes the apoptosis process just like KU-55933 on myeloma cell lines when 0.61 μM concentration is used. This compound has been found effective in in-vivo and in-vitro conditions against different tumor models. Intrinsic and extrinsic pathways are activated following the apoptosis of cells. It is responsible for the cleavage of caspase-3, 8 and caspase-9. It is also reported that cytochrome c is released from mitochondria [1].
In addition to this HDAC-42 targets the cell signaling pathways which are important for cell survival. Signaling pathway of NF-κB and Akt phosphorylation are down regulated as it is a kinase inhibitor. All of these findings suggested that this inhibitor has a vital role in cell cycle progression [1].
HISTONES AND TUBULIN RESPONSE
Both proteins, histone H3 and class II target tubulin are acetylated by HDAC-42 in a dose dependant manner [2]. A sixty minutes exposure resulted in the hypermethylation of histone H3, histone H4 and α-tubulinin in the following cell lines - C2, P815 and BR as well as canine BMCMCs [3].
TNF-RELATED APOPTOSIS
HDAC-42 have an inducer effect on TRAIL (TNF-related apoptosis-inducing ligand) and it reduces c-FLIP levels, where c-FLIP is a protein which inhibits the caspase-8 e and when its level is reduced it leads to the production of TRAIL ligand. All these effects ultimately switch to TNF-Related Apoptosis in chronic lymphocytic leukemia cell lines [2].
INHIBTION OF CELL PROLIFERATION
Inhibition of cell proliferation by HDAC-42 is done in a dose dependent manner as in case of belinostat. During cell death studies of P815 cell lines it was reported that HDAC-42 arrest the growth of cells by arresting the cell cycle at G1 stage. While during same studies of C2 cells the cell cycle was arrested at both G1/G2 stages resulted in the death of large numbers of cells.
This compound also has the ability to induce caspase-3/7 activity which leads to apoptosis. However it is ineffective against the levels of Bcl-xL and Bcl-2 proteins. Hence these findings tell that this inhibitor does not have any effect on Bcl-2 mediated pathways which lead to apoptosis [3].
EFFECT ON KIT expression
HDAC-42 also reduces the phosphorylation and total Kit level when incubated for 24 hours. It is an effecter of Kit expression and in addition to this it also initiates the dissociation between HSP90 chaperon and Kit. Its effects on the acetylation of different histone proteins is also reported [3].
EFFECT ON THE EXPRESSION OF AKT TRANSCRIPTION FACTORS
Proliferation and viability of mast cells is regulated by Akt transcriptional factors. Like Kit HDAC-42 also reduces the levels of total as well as phosphorylated Akt. Different transcription factors of Akt one of which is p-STAT3 in BR, canine BMCMCs and in C2 cell lines are also reduced by HDAC-42. In case of BR cell lines the effect is different. The p-STAT5 and total STAT5 levels were down regulated while STATE3 transcription level remained the same.
CONCLUSION
AR-42 serves as a strong inhibitor of various transcriptional factors involved in cell cycle, ceasing the growth of cancer cells. Apoptosis process is controlled by affecting different pathways like tumor necrosis factor (TNF) induces pathway and ultimately leading to the death of cells. Hence this inhibitor can play a significant role in the inhibition of various cancer cells.
REFERENCES
1. Bai LY, Omar HA, et al. Antitumor effects of (S)-HDAC42, a phenylbutyrate-derived histone deacetylase inhibitor, in multiple myeloma cells. Cancer Chemother Pharmacol 2011 Aug; 68(2):489-96.
2. Lucas DM, Alinari L, et al. The Novel Deacetylase Inhibitor AR-42 Demonstrates Pre-Clinical Activity in B-Cell Malignancies In Vitro and In Vivo. PLoS One 2010 Jun 3; 5(6):e10941.
3. Lin TY, Fenger J, et al. AR-42, a novel HDAC inhibitor, exhibits biologic activity against malignant mast cell lines via down-regulation of constitutively activated Kit. Blood 2010 May 27; 115(21):4217-25.
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