Abstract
We illustrate the use of quantitative proteomics, namely isotope-coded affinity tag labelling and tandem mass spectrometry, to assess the targets and effects of the blockade of matrix metalloproteinases by an inhibitor drug in a breast cancer cell culture system. Treatment of MT1-MMP-transfected MDA-MB-231 cells with AG3340 (Prinomastat) directly affected the processing a multitude of matrix metalloproteinase substrates, and indirectly altered the expression of an array of other proteins with diverse functions. Therefore, broad spectrum blockade of MMPs has wide-ranging biological consequences. In this human breast cancer cell line, secreted substrates accumulated uncleaved in the conditioned medium and plasma membrane protein substrates were retained on the cell surface, due to reduced processing and shedding of these proteins (cell surface receptors, growth factors and bioactive molecules) to the medium in the presence of the matrix metalloproteinase inhibitor. Hence, proteomic investigation of drug-perturbed cellular proteomes can identify new protease substrates and at the same time provides valuable information for target validation, drug efficacy and potential side effects prior to commitment to clinical trials.
Keywords: Protease, anti-proteolytic drugs, MMP, proteomics, degradomics, pharmacoproteomics, ICAT, side effects
Current Pharmaceutical Design
Title: Proteomic Validation of Protease Drug Targets: Pharmacoproteomics of Matrix Metalloproteinase Inhibitor Drugs Using Isotope-Coded Affinity Tag Labelling and Tandem Mass Spectrometry
Volume: 13 Issue: 3
Author(s): G. S. Butler and C. M. Overall
Affiliation:
Keywords: Protease, anti-proteolytic drugs, MMP, proteomics, degradomics, pharmacoproteomics, ICAT, side effects
Abstract: We illustrate the use of quantitative proteomics, namely isotope-coded affinity tag labelling and tandem mass spectrometry, to assess the targets and effects of the blockade of matrix metalloproteinases by an inhibitor drug in a breast cancer cell culture system. Treatment of MT1-MMP-transfected MDA-MB-231 cells with AG3340 (Prinomastat) directly affected the processing a multitude of matrix metalloproteinase substrates, and indirectly altered the expression of an array of other proteins with diverse functions. Therefore, broad spectrum blockade of MMPs has wide-ranging biological consequences. In this human breast cancer cell line, secreted substrates accumulated uncleaved in the conditioned medium and plasma membrane protein substrates were retained on the cell surface, due to reduced processing and shedding of these proteins (cell surface receptors, growth factors and bioactive molecules) to the medium in the presence of the matrix metalloproteinase inhibitor. Hence, proteomic investigation of drug-perturbed cellular proteomes can identify new protease substrates and at the same time provides valuable information for target validation, drug efficacy and potential side effects prior to commitment to clinical trials.
Export Options
About this article
Cite this article as:
Butler S. G. and Overall M. C., Proteomic Validation of Protease Drug Targets: Pharmacoproteomics of Matrix Metalloproteinase Inhibitor Drugs Using Isotope-Coded Affinity Tag Labelling and Tandem Mass Spectrometry, Current Pharmaceutical Design 2007; 13 (3) . https://dx.doi.org/10.2174/138161207779313524
DOI https://dx.doi.org/10.2174/138161207779313524 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Herbal Nano Formulations: Patent and Regulatory Overview
Applied Clinical Research, Clinical Trials and Regulatory Affairs Engineered E. coli as Vehicles for Targeted Therapeutics
Current Gene Therapy Genetics of Serotonin Receptors and Depression: State of the Art
Current Drug Targets Meet Our Editorial Board Member
Letters in Drug Design & Discovery Understanding Membrane Protein Drug Targets in Computational Perspective
Current Drug Targets In Vitro - In Vivo Correlation of Gene Expression Alterations Induced by Liver Carcinogens
Current Medicinal Chemistry GMDR: Versatile Software for Detecting Gene-Gene and Gene-Environment Interactions Underlying Complex Traits
Current Genomics Estrogen Receptors: Molecular Interactions, Virtual Screening and Future Prospects
Current Topics in Medicinal Chemistry Enzyme-responsive Nanoparticles for Anticancer Drug Delivery
Current Nanoscience Flavonoids as Anticancer Agents: Structure-Activity Relationship Study
Current Medicinal Chemistry - Anti-Cancer Agents Effects of Radiation on Drug Metabolism: A Review
Current Drug Metabolism CatbNet: A Multi Network Analyzer for Comparing and Analyzing the Topology of Biological Networks
Current Genomics Inhibitors for Metastasis Development
Recent Patents on Anti-Cancer Drug Discovery Folic Acid Conjugated Chitosan Nanoparticles for Tumor Targeting of Therapeutic and Imaging Agents
Pharmaceutical Nanotechnology The Value of Elastosonography in Evaluation of Thyroid Nodules
Recent Patents on Medical Imaging Phosphoinositide 3-Kinases as Targets for Therapeutic Intervention
Current Pharmaceutical Design The Therapeutic Impact of Manipulating Microbiota in Inflammatory Bowel Disease
Current Pharmaceutical Design The Role of Mast Cells in the Structural Alterations of the Airways as a Potential Mechanism in the Pathogenesis of Severe Asthma
Current Pharmaceutical Design Telomere Maintenance Mechanisms in Cancer: Clinical Implications
Current Pharmaceutical Design Basal Breast Cancer: A Complex and Deadly Molecular Subtype
Current Molecular Medicine