BORTEZOMIB – THE FIRST PROTEASOME INHIBITOR

Introduction: Inhibition of the Proteasomes

In the cellular environment there is a continuous movement of cells through cycles of life and death. Material is up taken and used to create new cells or energy, while protein signaling cascades regulate everything so that the host organism survives. However, during these essential processes proteins become damaged, unraveled or simply surplus to requirements, in this situation there exists clean up mechanisms to recycle as much material as possible. The major (>80%) pathway for this process is the proteasome pathway which in conjunction with the Ubiquitin pathway performs clean up routines in the cellular environment. The proteasome is a tubular protein sealed with another protein containing a tyrosine kinase domain. This tubular protein allows “tagged” protein to enter and bind within the tube section. Then catalytic activity begins to dismantle the protein and pass subunits out into the cytosole for reuse. Protein are recognized for destruction due to the actions of the Ubiquitin protein kinases. These proteins poly – ubiquitinate other proteins that are recognized as bringing damaged in some way or are surpluss to requirements. This tagging induces the protein move to the proteasome tubular initiating the destructive sequence. Inhibition of the proteasome would stop this cellular clean up which in turn would lead to the accumulation of unwanted protein structures, this contamination of the cell would in turn trigger the apoptotic effect and the cell would die. The significance of this would be that since tumor cells grow so quickly and dominate the nutritional up take they would be more seriously affected rather than the normal cells. Inhibition of the proteasome was first clinically used by a boric acid derivative with the trade name Bortezomib.

Bortezomib: Properties and availability

As already indicated Bortezomib structure has a boric acid moiety contained with it that is directly linked to activity in certain tumor cell lines. 

Bortezomib IC50 is a very well-known, highly specific and selective boronate proteasome inhibitor, the first one to be used in human clinical trials for multiple myeloma patients. reveals that it is a boronic acid derivative with the boron atom playing a significant role in its mode of action. are usually high and are around $2000 for 1000 mg and varies from one Bortezomib supplier to other, depending on its percentage purity. in water is very less but in organic solvents like DMSO and ethanol, a 200mg/ml solution of Bortezomib can be easily made. is around 10 nM for effective proteasome inhibition.

 

BORTEZOMIB – MECHANISM OF ACTION:

Bortezomib proteasome inhibitor brings about proteasome inhibition by the very specific binding of its boron atom to 26S proteasome rendering its catalytic site inactive. This reversible binding is largely ineffective in case of normal cells thus sparing them from induced apoptosis, but in neoplastic cells the proteasome inhibition leads to the apoptosis of cancer cells [1]. A point mutation (G322A) in β5 subunit of proteasome can be crucial as introduction of this mutation overcomes Bortezomib-induced resistance in lymphoma and leukemic cells [2]thus throwing some light on its mechanism of action. In renal cell cancer, blocking the constitutionally active NF-kB pathway of cell survival and cell proliferation, was reported to enhance Bortezomib induced apoptosis [3] and an independent study threw more light on Bortezomib mechanism stating that it achieves this NF-kB down-regulation through either a p21 dependent action in human prostate cancer and bladder cells [4] or by affecting the apoptosis inducing TNF related apoptosis inducing ligand (TRAIL) pathway in prostate cancer cases [5].

 

 

BORTEZOMIB IN CLINICAL TRIALS:

A high clearance rate of Bortezomib post-intravenous administration as discovered during its pharmacokinetic studies, is a fact that goes in favor of using it in clinical trials [6]. A gene expression profile and clinical outcome assessment study using Bortezomib in phase II and III trials involving human lymphoma cancer patients consolidated its reputation of having an excellent safety profile and efficiency inBortezomib clinical trials [7] after its success in a phase II study in refractory or relapsed lymphoma patients [8]. It has been used in phase I clinical trial of prostate cancer cases also [9]. Though Bortezomib clinical trials tasted most success in multiple myeloma cases [10], various clinical trials proved an increased efficacy of Bortezomib upon its co-treatment with other pharmaceutical compounds like thalidomide, Vascular Endothelial Growth Factor (VEGF) inhibitors, Lenalidomide or arsenic trioxide etc. [11-12] and it had synergistic effect on killing myeloma cancer cells in culture when given in combination with Thapsigargin [13] or various Histone Deacetylases (HDAC) inhibitors in pancreatic cancer cells [14] or Celecoxib in glioma cells [15] though these claims are yet to be tested in clinical trials. 

 

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.