In VX-745is the p38 it is responsible for the stimulation of various inflammatory responses
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Posted On :
Jan-16-2012
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Article Word Count :
849
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There are good numbers of intracellular signaling pathways are activated in response to extracellular stimuli. Amongst all these important signaling pathways the MAPK (kinase of mitogen activated protein) is one of the vital pathways. In this it the p38 it is responsible for the stimulation of various inflammatory responses by activating the inflammatory mediators. Kinase inhibitors are very effective against the it pathway.
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INTRODUCTION:
There are good numbers of intracellular signaling pathways are activated in response to extracellular stimuli. Amongst all these important signaling pathways the MAPK (kinase of mitogen activated protein) is one of the vital pathways. In this it the p38 it is responsible for the stimulation of various inflammatory responses by activating the inflammatory mediators. Kinase inhibitors are very effective against the it pathway. Large number of these kinases is present and can be used with some of the approved agents (Abiraterone) and under clinical phase II kinases (Sunitinib and HKI-272).VX-745 is one of the it inhibitor which is specific in blocking the functions of p38 it, hence performing as anti-inflammatory agent.
Recently it has found that p38 it is present in four different isoforms which are p38?, p38?, p38? and p38? [1]. Unlike VX-702, VX-745 was reported to inhibit the three isoforms of p38 it which are p38?, p38?, p38? [2]. The effect on the p38? it was not appreciated able during certain experimental studies. Hence it is comparatively more potent than other p38 it inhibitors. A sit targets the multiple isoforms of the p38 it. These isoforms are inhibited by VX-745 which eventually inhibits the growth of cancerous cells and the inflammations are also decreased. This agent can also be used along with other angiogenesis inhibitors to enhance the death of cancer or tumor cells.
The patients having high levels of inflammations also have high levels of tumor necrosis factor- ? (TNF- ?). The TNF- ? is controlled by mitogen activated protein p38 kinase in two different ways, including the transcriptional control via NF-?B and also at translational level by 3′UTR of TNF-? [3]. As VX-745 specifically targets p38 it hence it has potential to control the cytokines (interleukin-1 and TNF-?) levels in the cell thereby decreasing the inflammatory agents [2]. In addition to this the amount of interleukin-6 in BMSCs (bone marrow stromal cells) are also checked by this inhibitor as IL-6 is stimulated by TNF-? [4]. Therefore this VX-745 plays an important role in the reduction of cytokines effects.
Nitric oxide and eicosanoids are released due to the action of certain enzymes including iNOS (nitric oxide synthase) and cyclooxygenase, at the site of inflammation. The production of inflammatory enzymes and MMP2, NNP9 and MMP13 which are metalloproteinases is regulated by p38-? it [5]. It shows the vital funtoins of p38 it enzyme in the tumor and cancer growth. VX-745 inhibits the activity of p38-? and inflammatory immune responses are controlled.
Interleukin-6 a cytokine is involved in the growth of MM (multiple myeloma) cancer cells on the other hand VEGF (vascular endothelial growth factor) plays a function in proliferation of tumor cells. These secretions of cytokines are stimulated by the attachment of BMSCs to MM cells. Interleukin-6 (IL-6) expression is enhanced by the BMSCs. The patients with multiple myeloma are found to have lower IL-6 levels in BMSCs due to the inhibitory effects of VX-745 [4].
CONCLUSION
A strong anti-cancer agent and inhibits p38 MAPK, VX-745 checks multiple signaling pathways which are the causes of inflammatory responses. This agent is currently undergoing the evaluation of clinical trials phase II. During these trials it has been noticed that the inflammations were reduced due to the action of this molecule. VX-745 controls the inflammations because of its specific action on the p38 it. This compound is helpful in controlling the multiple myeloma and other inflammatory cancer response.
REFERENCES
1. Schett G, Smolen JS, et al. Activation and signaling of the p38 it pathway. Arthritis Rheum 2000 Nov; 43(11):2501-12.
2. Haddad JJ. VX-745. Vertex Pharmaceuticals. Curr Opin Investig Drugs 2001 Aug; 2(8):1070-6.
3. Campbell J, Cathleen J. et al. A Novel Mechanism for TNF-? Regulation by p38 MAPK: Involvement of NF-?B with Implications for Therapy in Rheumatoid Arthritis1. The Journal of Immunology 2004; 173: 6928-6937.
4. Hideshima T, Akiyama M, et al. Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu. Blood 2003 Jan 15; 101(2):703-5.
5. Schindler JF, Monahan JB, Smith WG. p38 Pathway Kinases as Anti-inflammatory Drug Targets. J Dent Res 2007 Sep; 86(9):800-11.
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