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BORTEZOMIB: AN ANTI-PROTEIN DEGRADATION AGENT

by Rabia Javed | Jun 20 2012

BORTEZOMIB
Proteasomes belong to one of the important small organelles present in cell. Cell cycle is regulated by these proteasomes as they remove any unnecessary protein from cell. Usually during the cancer state the proteins which inhibit uncontrolled cell development of cancer are chopped down by these proteasomes. To stop chop these abnormal proteins properly inhibition of proteasomes is necessary which offers a good target for cancer therapy. For cancer treatment a lot of various compounds are being employed that cause proteasomes inhibition for example e.g., green tea having Epigallocatechin-3-gallate (EGCG), Salinosporamide-A and Disulfiram. Bortezomib was entitled to be first inhibitor that got approval to enter clinical studies for treatment of cancer.
Bortezomib which is boronate inhibitor inhibits proteasome which is very specific against the target compound. It is marketed under the trade name of Bortezomib PS-34 or Velcade. This was the first inhibitor of proteasomes that entered clinical studies against multiple myeloma cells. Bortezomib structure showed that it contained boron atom and boric acid which is predicted to have efficient role in its action. Anyone can purchase Bortezomib at the rate of $2000 per 1000mg of vial. Bortezomib price varies among different Bortezomib supplier. It is soluble in DMSO with for Bortezomib solubility of 200mg/ml however it is poorly soluble in water. Bortezomib IC50 is 10 nM and promising results are obtained.


BORTEZOMIB MODE OF PERFORMING FUNCTIONS
When Bortezomib proteasome inhibitor was administered to various types of cancers, very positive results were obtained. Boron atoms of the medicine play important in interaction with proteasome. Bortezomib is specific in its target as only binding sites are available in cancer cell not in normal cells so it does not interact and effect 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] and hence Bortezomib’s mechanism of action was evaluated by this study. Bortezomib was found to inhibit NF-k Bcascade which is involved in the proliferation and survival of renal cancer cells so inhibition of this cascade caused apoptosis of cells [3]. Evaluation of mechanism of action of Bortezomib was conducted by in vivo studies in human having prostate/bladder cancer and in vitro studies were done inprostate cancer cell lines. It 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 STUDIES OF BORTEZOMIB
Bortezomib in its pharmacokinetic studies showed that it has high rate of clearance after post-intravenous injection [6] which supported to conduct clinical trials. In phase II and III clinical trials on patients suffering lymphoma showed good safety and efficiency results about Bortezomib and also 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]. Clinical trials phase I on patients of prostate cancer also showed good results [9]. When given in combination with other drugs such as arsenic oxide or thalidomide and VEGF inhibitor it was shown to havemore efficient results in multiple myeloma cells [13].Similar type of study was also conducted on pancreatic cancer cells by giving Bortezomib in combination with some inhibitors of histone deacetylases (HDACs) [14] as well as 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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