One of the most important categories of enzymes in the cell is the protein degrading enzymes called as proteosomes. They degrade all types of un-wanted proteins in the cells hence can regulate some important pathways in the cells like gene expression and cell cycle. The compounds which obstruct the activity of these enzymes play an important role in process of inhibition of degradation of cancer inhibiting proteins. Due to these properties proteosome inhibiting molecules like EGCG (Epigallocatechin-3-gallate) known as green tea as well, Disulfiram and Salinosporamide-A have been found to use for treatment of cancer. The first approved proteosomal inhibiting drug for clinical studies is Bortezomib and it is a very famous inhibitor of this class of enzymes.
Bortezomib is a well known, highly recognized and very specific and selective boronate proteosome inhibitor molecule. Its code name is PS-341 and it is marketed under the name PS-341 Velcade. In multiple myeloma patients it was first proteosome inhibiting drug used in clinical trials. Structure of Bortezomib proteasome inhibitor is based upon boric acid and the boron atom plays a key role in its function. One can purchase PS-341 (Bortezomib) 1000 mg vial from any of supplier PS-341 by paying its price around $2000. PS-341 price is not fix, it varies from supplier to supplier. PS-341 solubility is very good in organic solvents like DMSO and ethanol but is insoluble in water. It gives 200 mg/ml solution in DMSO easily. PS-341 IC50 is found to be 10 nM for more efficient results.

PS-341 proteosome inhibitor plays inhibitory role by a specific interaction by using its boron atom 26S proteosome on the behalf of its active site inactive. The binding is ineffective and not so rigid in normal cells and in neoplastic cells this sort of inhibition triggers the apoptotic cell death [1]. In lymphoma and leukemia cell lines it has been found that the subunit β5 of proteosome rendering a point mutation, G322A can be valuable because due to this mutation PS-341-induced resistance can be overcome [2] hence this study has elaborated the mode of action of PS-341 proteosome inhibitor. In case of renal cancer, inhibition of the NF-kB cascade of cell survival and proliferation was found to be helpful in Bortezomib induced apoptotic cell death [3]. Another study revealed that the mode of action of PS-341 also depends upon down regulation NF-kB pathway via either targeting the induction of apoptosis by TNF in TRIAL cascade to cease prostate cancer [5] or by action of p21 gene in human bladder or prostate tumor cell lines. 

In pharmacokinetic analysis of Bortezomib or PS-341 it was observed that clearance rate of this inhibitor is very high in case of post-intravenous administration and these properties lead PS-341 to clinical trials [6]. The outcome of PS-341 clinical trial in lymphoma patients and the genetic expression profiling during phase II and phase III clinical trials has made its reputation of containing very good safety profile and efficacy [7] and these results were based upon the evaluations of clinical trials of phase II in patients of refractory or relapsed lymphoma [8]. PS-341 has also been found to use against prostate cancer cell lines in clinical studies of phase I [9]. Although bortezomib alone is found to be a very effective and valuable in multiple myeloma trials but according to many other studies this inhibitor works very well in combination with some other anti tumor agents like VEGF inhibitors, arsenic trioxide and thalidomide [11-12] and had also shown synergistic effects when used along Thapsigargin on myeloma cell lines [13], with some histone deacetylase inhibitors (HDACs) in pancreatic cancer cell lines [14], with Celecoxib in glioma [15].

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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