Abstract
Altered EGFR activity is a causal factor for human tumor development, including malignant pleural mesotheliomas. The aim of the present study was the evaluation of the effects of Gefitinib on EGF-induced mesothelioma cell proliferation and the intracellular mechanisms involved. Cell proliferation, DNA synthesis and apoptosis were measured by MTT, thymidine incorporation and FACS analysis; EGFR, ERK1/2 and Akt expression and phosphorylation by Western blot, whereas receptor sites were analyzed by binding studies. Gefitinib inhibited EGF-induced proliferation in two mesothelioma cell lines, derived from pleural effusion (IST-Mes2) or tumor biopsy (ZL55). The treatment with Gefitinib induced cell cycle arrest in both cell lines, while apoptosis was observed only for high concentrations and prolonged drug exposure. EGF-dependent mesothelioma cell proliferation was mediated by EGFR and ERK1/2 phosphorylation, while Akt was not affected. Gefitinib inhibited both EGFR and ERK1/2 activation, being maximal at drug concentrations that induce cytostatic effects, suggesting that the proapoptotic activity of Gefitinib is independent from EGFR inhibition. Gefitinib treatment increased EGFR Bmax, possibly through membrane stabilization of inactive receptor dimers that we show to be induced by the drug also in the absence of EGF. EGFR activation of ERK1/2 represents a key pathway for pleural mesothelioma cell proliferation. Low concentrations of Gefitinib cause mesothelioma cell cycle arrest through the blockade of EGFR activity while high concentrations induce apoptosis. Finally, we propose that the formation of inactive EGFR dimers may contribute to the antitumoral activity of Gefitinib.
Keywords: Human malignant pleural mesothelioma cells, EGFR targeting, Gefitinib, preclinical chemotherapy
Current Cancer Drug Targets
Title: Gefitinib Targets EGFR Dimerization and ERK1/2 Phosphorylation to Inhibit Pleural Mesothelioma Cell Proliferation
Volume: 10 Issue: 2
Author(s): R. E. Favoni, A. Pattarozzi, M. Lo Casto, F. Barbieri, M. Gatti, L. Paleari, A. Bajetto, C. Porcile, G. Gaudino, L. Mutti, G. Corte, T. Florio and M. Casto
Affiliation:
Keywords: Human malignant pleural mesothelioma cells, EGFR targeting, Gefitinib, preclinical chemotherapy
Abstract: Altered EGFR activity is a causal factor for human tumor development, including malignant pleural mesotheliomas. The aim of the present study was the evaluation of the effects of Gefitinib on EGF-induced mesothelioma cell proliferation and the intracellular mechanisms involved. Cell proliferation, DNA synthesis and apoptosis were measured by MTT, thymidine incorporation and FACS analysis; EGFR, ERK1/2 and Akt expression and phosphorylation by Western blot, whereas receptor sites were analyzed by binding studies. Gefitinib inhibited EGF-induced proliferation in two mesothelioma cell lines, derived from pleural effusion (IST-Mes2) or tumor biopsy (ZL55). The treatment with Gefitinib induced cell cycle arrest in both cell lines, while apoptosis was observed only for high concentrations and prolonged drug exposure. EGF-dependent mesothelioma cell proliferation was mediated by EGFR and ERK1/2 phosphorylation, while Akt was not affected. Gefitinib inhibited both EGFR and ERK1/2 activation, being maximal at drug concentrations that induce cytostatic effects, suggesting that the proapoptotic activity of Gefitinib is independent from EGFR inhibition. Gefitinib treatment increased EGFR Bmax, possibly through membrane stabilization of inactive receptor dimers that we show to be induced by the drug also in the absence of EGF. EGFR activation of ERK1/2 represents a key pathway for pleural mesothelioma cell proliferation. Low concentrations of Gefitinib cause mesothelioma cell cycle arrest through the blockade of EGFR activity while high concentrations induce apoptosis. Finally, we propose that the formation of inactive EGFR dimers may contribute to the antitumoral activity of Gefitinib.
Export Options
About this article
Cite this article as:
E. Favoni R., Pattarozzi A., Casto Lo M., Barbieri F., Gatti M., Paleari L., Bajetto A., Porcile C., Gaudino G., Mutti L., Corte G., Florio T. and Casto M., Gefitinib Targets EGFR Dimerization and ERK1/2 Phosphorylation to Inhibit Pleural Mesothelioma Cell Proliferation, Current Cancer Drug Targets 2010; 10 (2) . https://dx.doi.org/10.2174/156800910791054130
DOI https://dx.doi.org/10.2174/156800910791054130 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...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
Related Articles
-
Comparative Proteomics and Bioinformatics Analysis of Tissue from Non-Small Cell Lung Cancer Patients
Current Proteomics From French Paradox to Cancer Treatment: Anti-cancer Activities and Mechanisms of Resveratrol
Anti-Cancer Agents in Medicinal Chemistry Tumor Control by Manipulation of the Human Anti-Apoptotic Survivin Gene
Current Cancer Therapy Reviews Targeting Neuronal Nicotinic Receptors in Cancer: New Ligands and Potential Side-Effects
Recent Patents on Anti-Cancer Drug Discovery Rediscovering Tocophersolan: A Renaissance for Nano-Based Drug Delivery and Nanotheranostic Applications
Current Drug Targets Mitocans: Mitochondrial Targeted Anti-Cancer Drugs as Improved Therapies and Related Patent Documents
Recent Patents on Anti-Cancer Drug Discovery Current Molecularly Targeting Therapies in NSCLC and Melanoma
Anti-Cancer Agents in Medicinal Chemistry Carbon Nanotube: A Versatile Carrier for Various Biomedical Applications
Drug Delivery Letters The Means to an End of Tumor Cell Resistance to Chemotherapeutic Drugs Targeting Thymidylate Synthase: Shoot the Messenger
Current Drug Targets The Drug Targeting and Delivery Approach Applied to Pt-Antitumour Complexes. A Coordination Point of View
Current Medicinal Chemistry Research Toward Potassium Channels on Tumor Progression
Current Topics in Medicinal Chemistry Lipoxygenase Inhibitors for Cancer Prevention: Promises and Risks
Current Pharmaceutical Design Malignant Mesothelioma Resistance to Apoptosis: Recent Discoveries and their Implication for Effective Therapeutic Strategies
Current Medicinal Chemistry Evasion of Ribonuclease Inhibitor as a Determinant of Ribonuclease Cytotoxicity
Current Pharmaceutical Biotechnology Quantum Dot-Based Nanoprobes for In Vivo Targeted Imaging
Current Molecular Medicine α7 nAChR in Airway Respiratory Epithelial Cells
Current Drug Targets Inflammation and Pancreatic Cancer: Recent Development with Focusing on Potential New Drug Targets
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Targeting the Most Upstream Site of Wnt Signaling Pathway Provides a Strategic Advantage for Therapy in Colorectal Cancer
Current Drug Targets Drug Repurposing Screen Identifies Novel Classes of Drugs with Anticancer Activity in Mantle Cell Lymphoma
Combinatorial Chemistry & High Throughput Screening DNA Methylation Markers in Lung Cancer
Current Genomics