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
Innovative Cancer Drug Targets: A New Horizon in Oncology
Cancer remains one of the most challenging diseases, with its complexity and adaptability necessitating continuous research efforts into more effective and targeted therapeutic approaches. Recent years have witnessed significant progress in understanding the molecular and genetic basis of cancer, leading to the identification of novel drug targets. These include, but ...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
![](/images/wayfinder.jpg)
- 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
-
An Update on the Other Telomerase Inhibitors: Non-G-Quadruplex Interactive Agent, Non-Antisense, Non-Reverse Transcriptase Telomerase Inhibitors
Medicinal Chemistry Reviews - Online (Discontinued) Cell-in-cell phenomenon: A New Paradigm in Life Sciences.
Current Molecular Medicine Sequential Bilateral Internal Jugular Vein Thrombosis: A Case Report and Review of this Rare Medical Entity
Vascular Disease Prevention (Discontinued) Advancements in the Research of GEF-H1: Biological Functions and Tumor Associations
Current Molecular Pharmacology Pathway of Inflammation due to Asbestiform Fiber “Fluoro-edenite” Exposure: An Update
Current Respiratory Medicine Reviews Intracellular Bioinorganic Chemistry and Cross Talk Among Different -Omics
Current Topics in Medicinal Chemistry Metastasis Suppressors: Basic and Translational Advances
Current Pharmaceutical Biotechnology The Means to an End of Tumor Cell Resistance to Chemotherapeutic Drugs Targeting Thymidylate Synthase: Shoot the Messenger
Current Drug Targets Liposomes: An Emerging Approach for the Treatment of Cancer
Current Pharmaceutical Design Metallodrugs in Targeted Cancer Therapeutics: Aiming at Chemoresistance- related Patterns and Immunosuppressive Tumor Networks
Current Medicinal Chemistry Patent Selections
Recent Patents on Biomarkers Enhancement of the Antiproliferative Activity of Gemcitabine by Modulation of c-Met Pathway in Pancreatic Cancer
Current Pharmaceutical Design Biomarkers of Protein Oxidation in Human Disease
Current Molecular Medicine Amino Acid Degrading Enzymes and their Application in Cancer Therapy
Current Medicinal Chemistry Histone Deacetylase Inhibitors: A New Wave of Molecular Targeted Anticancer Agents
Recent Patents on Anti-Cancer Drug Discovery Toward The Rational Design of Cell Fate Modifiers Notch Signaling as a Target for Novel Biopharmaceuticals
Current Pharmaceutical Biotechnology A Better Platinum-Based Anticancer Drug Yet to Come?
Anti-Cancer Agents in Medicinal Chemistry 86Y Based PET Radiopharmaceuticals: Radiochemistry and Biological Applications
Medicinal Chemistry Epigenetic alterations as a universal feature of cancer hallmarks and a promising target for personalized treatments
Current Topics in Medicinal Chemistry The Phosphoinositide 3-Kinase Pathway in Human Cancer: Genetic Alterations and Therapeutic Implications
Current Genomics