Proteasome inhibitor against misfolded proteins
PROTEASOME PATHWAY:
Proteasomes degrade unneeded, damaged and misfolded proteins by performing proteolysis with the help of proteases enzymes to keep the proteins concentration in regulation. This process of maintain a particular protein concentration becomes crucial in normal conditions where the levels of proteins involved in cellular processes like cell cycle, gene expression etc. has to be maintained tightly to avoid their uncontrolled numbers that can lead to cancers. In regulation of cancers, thus proteasome inhibition plays a major role by inducing disrupting the regulated degradation of cell cycle proteins to induce apoptosis. Hence the use of a proteasome pathway inhibitor becomes an attractive approach to treat diseases which are associated with the misfolding of proteins and accumulation of such proteins leading to a pathological condition. The knowledge of proteasome inhibitor mechanism [1] of a number of molecules has facilitated their use for the aforementioned purpose.
PROPERTIES OF PROTEASOME INHIBITORS:
The development of a proteasome selective inhibitor is often aimed at efficient proteasome inhibition that can result in potent apoptosis of tumor cells. Apart from finding its use in targeting cancer, a proteasome inhibitor drug is seen to be effective in neurodegenerative diseases like Parkinson's and Alzheimer's disease. A proteasome antagonist and a proteasome agonist can be employed to assess the importance of this process in various conditions. The availability of such molecules is high and one can easily buy Proteasome inhibitor for research and laboratory purposes. Many kits are also available commercially to perform a proteasome inhibitor assay using a flourogenic substrate [2] to assess the level of proteasome activity in presence of a proteasome specific inhibitor. An example of a basic protease inhibitor assay is polyacrylamide gel electrophoretogram which facilitates the detection and qualitative measurement of protease inhibitors [3].
ASSESSMENT OF PROTEASOME INHIBITORS AT MULTIPLE LEVELS:
Bortezomib is the most well known proteasome inhibitor and was the first proteasome inhibitor in clinical trials to get FDA approval. It was seen to be well-tolerated with patients with slow malignancies and mantle-cell lymphoma (MCL) in phase II clinical trials [4] and its clinical outcome was correlated with the gene profiling successfully [5]. It also showed potent efficacy in a phase II study involving patients with relapsed or refractory form of B-Cell non-hodgkin's lymphoma (NHL) [6]. Bortezomib is known to have an even broader activity spectrum and it was seen to be very successful against advanced solid tumor cases in a phase I trial [7]. Prostate Cancer Disulfiram is another molecule that was used for clinical trials [8] after it generated good success in in vitro and in vivo models of cancers [9]. Another molecule PS-341 showed potent activity in patients suffering from refractory multiple myeloma (MM) and NHL in a phase I study [10] where its safety, tolerability, maximum tolerable dose and pharmacokinetics was determined. It was seen to be effective against advanced form of solid malignancies also in patients enrolled in a phase I trial [11]. Marizomib is a newly discovered and worked upon proteasome inhibitor and in combination with HDAC inhibitor Vorinostat, it shows good anti-tumor potency in a phase I trial involving melanoma, lung cancer and pancreatic cancer [12].
REFERENCES:
1. Elliott PJ, e.a., Proteasome inhibition: A novel mechanism to combat asthma. Journal of Allergy and Clinical Immunology, 1999.
2. Kuo CJ, e.a., Characterization of SARS main protease and inhibitor assay using a fluorogenic substrate. Biochem Biophys Res Commun, 2004.
3. Grenier, D., Assay for protease inhibitors: qualitative measurement and detection in polyacrylamide gel electrophoretograms. J Biochem Biophys Methods., 1991.
4. O'Connor OA, e.a., Phase II Clinical Experience With the Novel Proteasome Inhibitor Bortezomib in Patients With Indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma Journal of Clinical Oncology, 2005.
5. Mulligan G, e.a., Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib. Blood, 2007.
6. Goy A, e.a., Phase II Study of Proteasome Inhibitor Bortezomib in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma. Journal of Clinical Oncology, 2005.
7. Papandreou CN, 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, 224.
8. Cvek B, D.Z., The value of proteasome inhibition in cancer. Can the old drug, disulfiram, have a bright new future as a novel proteasome inhibitor? Drug Discovery Today, 2008.
9. Wickström M, e.a., Pharmacological profiling of disulfiram using human tumor cell lines and human tumor cells from patients. Biochemical Pharmacology, 2007.
10. Orlowski RZ, e.a., Phase I Trial of the Proteasome Inhibitor PS-341 in Patients With Refractory Hematologic Malignancies. Journal of Clinical Oncology, 2002.
11. Aghajanian C, e.a., A Phase I Trial of the Novel Proteasome Inhibitor PS341 in Advanced Solid Tumor Malignancies. Clin Cancer Res, 2002.
12. Millward M, e.a., Phase 1 clinical trial of the novel proteasome inhibitor marizomib with the histone deacetylase inhibitor vorinostat in patients with melanoma, pancreatic and lung cancer based on in vitro assessments of the combination. Investigational New Drugs, 2011.
Proteasomes degrade unneeded, damaged and misfolded proteins by performing proteolysis with the help of proteases enzymes to keep the proteins concentration in regulation. This process of maintain a particular protein concentration becomes crucial in normal conditions where the levels of proteins involved in cellular processes like cell cycle, gene expression etc. has to be maintained tightly to avoid their uncontrolled numbers that can lead to cancers. In regulation of cancers, thus proteasome inhibition plays a major role by inducing disrupting the regulated degradation of cell cycle proteins to induce apoptosis. Hence the use of a proteasome pathway inhibitor becomes an attractive approach to treat diseases which are associated with the misfolding of proteins and accumulation of such proteins leading to a pathological condition. The knowledge of proteasome inhibitor mechanism [1] of a number of molecules has facilitated their use for the aforementioned purpose.
PROPERTIES OF PROTEASOME INHIBITORS:
The development of a proteasome selective inhibitor is often aimed at efficient proteasome inhibition that can result in potent apoptosis of tumor cells. Apart from finding its use in targeting cancer, a proteasome inhibitor drug is seen to be effective in neurodegenerative diseases like Parkinson's and Alzheimer's disease. A proteasome antagonist and a proteasome agonist can be employed to assess the importance of this process in various conditions. The availability of such molecules is high and one can easily buy Proteasome inhibitor for research and laboratory purposes. Many kits are also available commercially to perform a proteasome inhibitor assay using a flourogenic substrate [2] to assess the level of proteasome activity in presence of a proteasome specific inhibitor. An example of a basic protease inhibitor assay is polyacrylamide gel electrophoretogram which facilitates the detection and qualitative measurement of protease inhibitors [3].
ASSESSMENT OF PROTEASOME INHIBITORS AT MULTIPLE LEVELS:
Bortezomib is the most well known proteasome inhibitor and was the first proteasome inhibitor in clinical trials to get FDA approval. It was seen to be well-tolerated with patients with slow malignancies and mantle-cell lymphoma (MCL) in phase II clinical trials [4] and its clinical outcome was correlated with the gene profiling successfully [5]. It also showed potent efficacy in a phase II study involving patients with relapsed or refractory form of B-Cell non-hodgkin's lymphoma (NHL) [6]. Bortezomib is known to have an even broader activity spectrum and it was seen to be very successful against advanced solid tumor cases in a phase I trial [7]. Prostate Cancer Disulfiram is another molecule that was used for clinical trials [8] after it generated good success in in vitro and in vivo models of cancers [9]. Another molecule PS-341 showed potent activity in patients suffering from refractory multiple myeloma (MM) and NHL in a phase I study [10] where its safety, tolerability, maximum tolerable dose and pharmacokinetics was determined. It was seen to be effective against advanced form of solid malignancies also in patients enrolled in a phase I trial [11]. Marizomib is a newly discovered and worked upon proteasome inhibitor and in combination with HDAC inhibitor Vorinostat, it shows good anti-tumor potency in a phase I trial involving melanoma, lung cancer and pancreatic cancer [12].
REFERENCES:
1. Elliott PJ, e.a., Proteasome inhibition: A novel mechanism to combat asthma. Journal of Allergy and Clinical Immunology, 1999.
2. Kuo CJ, e.a., Characterization of SARS main protease and inhibitor assay using a fluorogenic substrate. Biochem Biophys Res Commun, 2004.
3. Grenier, D., Assay for protease inhibitors: qualitative measurement and detection in polyacrylamide gel electrophoretograms. J Biochem Biophys Methods., 1991.
4. O'Connor OA, e.a., Phase II Clinical Experience With the Novel Proteasome Inhibitor Bortezomib in Patients With Indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma Journal of Clinical Oncology, 2005.
5. Mulligan G, e.a., Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib. Blood, 2007.
6. Goy A, e.a., Phase II Study of Proteasome Inhibitor Bortezomib in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma. Journal of Clinical Oncology, 2005.
7. Papandreou CN, 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, 224.
8. Cvek B, D.Z., The value of proteasome inhibition in cancer. Can the old drug, disulfiram, have a bright new future as a novel proteasome inhibitor? Drug Discovery Today, 2008.
9. Wickström M, e.a., Pharmacological profiling of disulfiram using human tumor cell lines and human tumor cells from patients. Biochemical Pharmacology, 2007.
10. Orlowski RZ, e.a., Phase I Trial of the Proteasome Inhibitor PS-341 in Patients With Refractory Hematologic Malignancies. Journal of Clinical Oncology, 2002.
11. Aghajanian C, e.a., A Phase I Trial of the Novel Proteasome Inhibitor PS341 in Advanced Solid Tumor Malignancies. Clin Cancer Res, 2002.
12. Millward M, e.a., Phase 1 clinical trial of the novel proteasome inhibitor marizomib with the histone deacetylase inhibitor vorinostat in patients with melanoma, pancreatic and lung cancer based on in vitro assessments of the combination. Investigational New Drugs, 2011.
Source...