BORTEZOMIB – A PROTEASOME INHIBITOR

by Selleckchem | Apr 10 2012

BORTEZOMIB:
There are different enzymes are present in the cell and amongst these enzymes Proteasomes are large enzymes which play function of degrading un-wanted proteins of cells, therefore these enzymes regulate some of the most important pathways including cell cycle and genetic expression. Those compounds which hinder the actions of these proteasomes play important functions in the process of inhibiting the degradation of tumor inhibiting proteins. Because of these properties the proteasome inhibitors such as EGCG (Epigallocatechin-3-gallate) also known as green tea, Salinosporamide-A and Disulfiram have been applied for cancer treatment. Bortezomib is the first approved proteasome inhibitor for clinical trials; this is the most famous inhibitor of this category.
Bortezomib is well recognized and highly selective and specific boronate proteasome inhibitor, in patients of multiple myeloma this was the first proteasome inhibitor to be used during clinical trials. The structure of Bortezomib proteasome inhibitor is based on boric acid and a boron atom plays an important role in its function. For a 1000 mg it costs around $2000 and this is not a fixed price and is variable depending upon its purity and Bortezomib supplier. One can buy Bortezomib from any of the supplier. This compound is soluble in most of organic solvents such as ethanol and DMSO but is poorly soluble in water; 200mg/ml of Bortezomib is made easily. For effective results Bortezomib IC50 is about 10 nM.

MODE OF ACTION OF BORTEZOMIB:
Bortezomib proteasome inhibitor plays its inhibitory tasks by a very specific interaction of its boron atom with 26S proteasome representing its active site inactive. In normal cells the binding is usually not rigid and is ineffective while in case of neoplastic cells this inhibition leads to the cell death by apoptosis [1]. In leukemic and lymphoma cells it has been reported that β5 subunit of proteasome having a point mutation G322A can be important as due to this mutation Bortezomib-induced resistance is overcome [2] and this study elaborate the mechanism of action of Bortezomib. In renal cancer, inhibiting the constitutionally the NF-B pathway of cell proliferation and survival was proved as helper in Bortezomib triggered apoptosis [3] and during another research it was shown that the mechanism of Bortezomib also depends on the NF-B down regulation via either p21 gene dependent action in human bladder and prostate cancer cells [4] or by targeting the apoptosis induction by TNF during TRAIL pathway in cases of prostate cancers [5].

CLINICAL TRIALS OF BORTEZOMIB
During pharmacokinetics studies of Bortezomib it was found as the clearance rate of this compound is high in post-intravenous administration, these properties lead Bortezomib to clinical trials [6]. Bortezomib clinical assessment outcome from patients of lymphoma and a genetic expression profile during clinical trials phase II and III fused its reputation of containing a very good efficacy and safety profile [7] and these were based on the clinical phase II evaluations of relapsed or refractory lymphoma patients [8]. Bortezomib has also been used for prostate cancer during its clinical phase I trials [9]. Although Bortezomib as alone has been used during clinical trials and proved to be very effective in multiple myeloma (MM) [10], many other clinical studies resulted about Bortezomib combination with other anticancer agents such as VEGF (Vascular Endothelial Growth Factor) inhibitors, thalidomide, arsenic trioxide and Lenalidomide [11-12] and it also had synergistic effect on myeloma cells during in-vitro study when used with Thapsigargin [13] and various HDAC (Histone Deacetylases) inhibitors when studied in cancer cells of pancreas [14], in glioma cells Celecoxib [15] though these results are yet be confirmed in clinical trials.

REFERENCES:
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