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BORTEZOMIB: AN INHIBITOR OF PROTEASOMAL DEGRADATION

BORTEZOMIB
Proteasomes are one of the very important small organelles present in the cell. They have an important role in cell cycle regulation by degrading un-necessary proteins present in the cell. Sometimes in cancerous cells, the proteins that play a role in inhibiting un-regulated proliferation of cells are degraded by proteasomes. Inhibition of proteasomes in order to inhibit un-regulated growth is an attractive target in cancer therapy. Different proteasome inhibiting compounds have been used conventionally for the treatment of cancer e.g.,green tea having Epigallocatechin-3-gallate (EGCG), Salinosporamide-A and Disulfiram. Bortezomib is the first proteasomal inhibitor that has got approval for clinical studies for the treatment of cancer.
Bortezomib is boronate inhibitor of proteasome and is a very selective and specific against the target compound. It is present in the shop as Bortezomib PS-341 or as Velcade. It was the first proteasome inhibitor that has been evaluated in clinical trials against multiple myeloma cells. Bortezomib structure contains boric acid in it and boron atom is considered to have an efficient role in its activity. Researchers or scientists can purchase Bortezomib in the form of a vial of 1000 mg in around $2000. Bortezomib price varies from one Bortezomib supplier to the other. Bortezomib solubility up to 200 mg/ml can be achieved in DMSO whereas no solubility has been seen in water. Bortezomib IC50 is 10 nM and gives quite efficient results.


BORTEZOMIB: MECHANISM OF ACTION
Bortezomib proteasome inhibitor has been found to be efficient in case of different types of cancers. Boron atoms play a role in its interaction against proteasome. Bortezomib is quite specific for neoplastic cells only due to its ability to have an effective binding only in these cells while it is rigid and ineffective in normal cells [1]. Proteasome G322A point mutation in subunit β5 has been found valuable in leukemia and lymphoma cell lines because it overcomes the resistance induced due to Bortezomib [2], therefore mechanism of action of the drug can be deduced from this study. NF-kB cascade that plays a role in the survival and proliferation of cell was inhibited in renal cancer cells and has been found to have an impact of cell death by apoptosis [3]. Mechanism of action of Bortezomib has also been studied in prostate cancer cells and human bladder/prostate cancer cells and has been observed to down regulate the NF-kB pathway by inducing apoptosis either by TNF in TRIAL cascade in the previous cell lines [5] or by the activity of p21 gene in the later cell lines. 


CLINICAL ASSESMENT OF BORTEZOMIB
Bortezomib in its pharmacokinetic analysis was observed to have a high rate of clearance if administered post-intravenously [6] these studies led it to clinical trials. The safety and efficacy was also found very good when studies were done on lymphoma patients in phase II and III clinical trials and their genetic expression profile was studied [7].This profiling was done after evaluation of studies done on refractory or relapsed cases of lymphoma in phase II clinical trials [8]. Bortezomib has also been studied in the cell lines of prostate cancer in phase I clinical trials [9]. Bortezomib has been studied alone effectively in multiple myeloma cells but it has also been seen to be efficient when studied in combination with other anti-cancer drugs e.g., VEGF inhibitors, thalidomide and arsenic trioxide [11-12] having synergistic effects with thapsigargin on the cell lines of myeloma [13]. Similar studies were done on pancreatic cell lines with combination of Bortezomib and some inhibitors of histone deacetylases (HDACs) [14] and on glioma cell lines with Celecoxib [15].


REFERENCES:
1. Rajkumar, S.V.e.a., Proteasome Inhibition As a Novel Therapeutic Target in Human Cancer. Journal of Clinical Oncology, 2005. 23(3): p. 630-63.
2. Lü, S.e.a., Point Mutation of the Proteasome β5 Subunit Gene Is an Important Mechanism of Bortezomib Resistance in Bortezomib-Selected Variants of Jurkat T Cell Lymphoblastic Lymphoma/Leukemia Line. Journal of Pharmacology and Experimental Therapeutics, 2008. 326(2): p. 423-431.
3. An, J.e.a., VHL expression in renal cell carcinoma sensitizes to bortezomib (PS-341) through an NF-kB-dependent mechanism. Oncogene, 2005. 24: p. 1563-1570.
4. Lashinger, L.M.e.a., Bortezomib Abolishes Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Resistance via a p21-Dependent Mechanism in Human Bladder and Prostate Cancer Cells. Cancer Res, 2005. 65: p. 4902.
5. Nikrad, M.e.a., The proteasome inhibitor Bortezomib sensitizes cells to killing by death receptor ligand TRAIL via BH3-only proteins Bik and Bim. Mol Cancer Ther, 2005. 4: p. 443.
6. Voorhees, P.M.e.a., The proteasome as a target for cancer therapy. Clin Cancer Res, 2003. 9(17): p. 6316-25.
7. Mulligan, G.e.a., Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor Bortezomib. Blood, 2007. 109: p. 3177-3188.
8. Fisher, R.I.e.a., Multicenter Phase II Study of Bortezomib in Patients With Relapsed or Refractory Mantle Cell Lymphoma. Journal of Clinical Oncology, 2006 24(30): p. 4867-4874.
9. Papandreou, C.N.e.a., Phase I Trial of the Proteasome Inhibitor Bortezomib in Patients With Advanced Solid Tumors With Observations in Androgen-Independent Prostate Cancer. Journal of Clinical Oncology, 2004. 22(11): p. 2108-2121.
10. Reeder, C.B.e.a., Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia, 2009. 23: p. 1337-1341.
11. Anargyrou, K.e.a., Novel anti-myeloma agents and angiogenesis. Leuk Lymphoma, 2008. 49(4): p. 677-689.
12. Richardson, P.G.e.a., Novel biological therapies for the treatment of multiple myeloma. Best Pract Res Clin Haematol, 2005. 18(4): p. 619-634.
13. Nawrocki, S.T.e.a., Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis. Cancer Res, 2005. 65(24): p. 11658-11666.
14. Nawrocki, S.T.e.a., Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res, 2006. 66(7): p. 3773-3781.
15. Kardosh, A.e.a., Aggravated endoplasmic reticulum stress as a basis for enhanced glioblastoma cell killing by bortezomib in combination with celecoxib or its non-coxib analogue, 2,5-dimethyl-celecoxib. Cancer Res, 2008. 68(3): p. 843-851.
 

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