Abstract
Alterations in tyrosine kinase expression or functionality have been linked to tumor growth, and detailed analysis of tyrosine kinase pathways has led to the development of novel anticancer drugs based on their inhibition. The aim of the present work was to examine the cytotoxicity and cellular alterations correlated with multidrug resistance mechanisms induced by three tyrosine kinase inhibitors, lapatinib, sorafenib and gefitinib. The study was performed on three breast cancer cell lines (BRC-230, MCF-7 and SkBr3). Drug-induced growth inhibition was detected by Sulforhodamine B analysis. Apoptosis, cytosolic calcium alteration, extrusion pump activity and mitochondrial membrane depolarization were assessed by flow cytometry. Drug efflux-related gene expression was analyzed by RT-PCR and drug target protein expression was evaluated by Western Blot. Lapatinib and gefitinib induced a cytotoxic effect and mitochondrial membrane depolarization in BRC-230 and SkBr3 cells, while sorafenib induced apoptosis and a high and rapid dissipation of mitochondrial potential in all cell lines. Moreover, all three drugs produced a rapid cytosolic calcium mobilization from endoplasmic reticulum stores in the investigated cell lines and a strong decrease in multidrug transporter activity in BRC- 230 and MCF-7 cells. Mitochondrial membrane depolarization and inhibition of multidrug transporter activity induced by tyrosine kinase inhibitors were independent of cytosolic calcium mobilization. These data suggest that the investigated drugs possess mechanisms of action that are independent of drug target expression, opening up further possibilities for the development of new therapeutic strategies.
Keywords: Tyrosine kinase inhibitor, breast cancer, in vitro study, calcium, multidrug resistance, mitochondrial depolarization, ABC transporters
Current Cancer Drug Targets
Title: Tyrosine Kinase Inhibitors Gefitinib, Lapatinib and Sorafenib Induce Rapid Functional Alterations in Breast Cancer Cells
Volume: 10 Issue: 4
Author(s): S. Carloni, F. Fabbri, G. Brigliadori, P. Ulivi, R. Silvestrini, D. Amadori and W. Zoli
Affiliation:
Keywords: Tyrosine kinase inhibitor, breast cancer, in vitro study, calcium, multidrug resistance, mitochondrial depolarization, ABC transporters
Abstract: Alterations in tyrosine kinase expression or functionality have been linked to tumor growth, and detailed analysis of tyrosine kinase pathways has led to the development of novel anticancer drugs based on their inhibition. The aim of the present work was to examine the cytotoxicity and cellular alterations correlated with multidrug resistance mechanisms induced by three tyrosine kinase inhibitors, lapatinib, sorafenib and gefitinib. The study was performed on three breast cancer cell lines (BRC-230, MCF-7 and SkBr3). Drug-induced growth inhibition was detected by Sulforhodamine B analysis. Apoptosis, cytosolic calcium alteration, extrusion pump activity and mitochondrial membrane depolarization were assessed by flow cytometry. Drug efflux-related gene expression was analyzed by RT-PCR and drug target protein expression was evaluated by Western Blot. Lapatinib and gefitinib induced a cytotoxic effect and mitochondrial membrane depolarization in BRC-230 and SkBr3 cells, while sorafenib induced apoptosis and a high and rapid dissipation of mitochondrial potential in all cell lines. Moreover, all three drugs produced a rapid cytosolic calcium mobilization from endoplasmic reticulum stores in the investigated cell lines and a strong decrease in multidrug transporter activity in BRC- 230 and MCF-7 cells. Mitochondrial membrane depolarization and inhibition of multidrug transporter activity induced by tyrosine kinase inhibitors were independent of cytosolic calcium mobilization. These data suggest that the investigated drugs possess mechanisms of action that are independent of drug target expression, opening up further possibilities for the development of new therapeutic strategies.
Export Options
About this article
Cite this article as:
Carloni S., Fabbri F., Brigliadori G., Ulivi P., Silvestrini R., Amadori D. and Zoli W., Tyrosine Kinase Inhibitors Gefitinib, Lapatinib and Sorafenib Induce Rapid Functional Alterations in Breast Cancer Cells, Current Cancer Drug Targets 2010; 10 (4) . https://dx.doi.org/10.2174/156800910791208580
DOI https://dx.doi.org/10.2174/156800910791208580 |
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
-
Molecular Phenotype of CXCL12β 3UTR G801A Polymorphism (rs1801157) Associated to HIV-1 Disease Progression
Current HIV Research Pitfalls and Solutions for the Validation of Novel Drugs in Animal Models of Disease
Current Immunology Reviews (Discontinued) Relationship Between Non-Genomic Actions of Estrogens and Insulin Resistace
Infectious Disorders - Drug Targets Genomics and the Prospects of Existing and Emerging Therapeutics for Cardiovascular Diseases
Current Pharmaceutical Design Breast Cancer Stem Cells and Sex Steroid Hormones
Current Stem Cell Research & Therapy Drugs and their Interactions
Current Drug Discovery Technologies Synthesis of Novel Pyridine Bearing Biologically Active Imidiazolyl, Pyrazolyl, Oxa/thiadiazolyl and Urea Derivatives as Promising Anticancer Agents
Current Organic Synthesis The miRNAs and Epithelial-Mesenchymal Transition in Cancers
Current Pharmaceutical Design Kefir: A Synbiotic with Approved Anticarcinogenic Properties
Current Bioactive Compounds Targeting Cancer Stem Cell Lines as a New Treatment of Human Cancer
Recent Patents on Anti-Cancer Drug Discovery The Prevention of Preterm Labour - Corticotropin Releasing Hormone Type 1 Receptors as a Target for Drug Design and Development
Mini-Reviews in Medicinal Chemistry Rapid Screening of Different Types of Antitumor Compound Groups from Traditional Chinese Medicine by Hollow Fiber Cell Fishing with High Performance Liquid Chromatography
Combinatorial Chemistry & High Throughput Screening Prospects of Applying Enhanced Semi-Empirical QM Methods for 2101 Virtual Drug Design
Current Medicinal Chemistry The Relation Between Stereochemistry and Biological Activity of Platinum(II) Complexes Chelated with Chiral Diamine Ligands: An Intricate Problem
Current Pharmaceutical Design Applications of High Content Screening in Life Science Research
Combinatorial Chemistry & High Throughput Screening Lipid based Nanocapsules: A Multitude of Biomedical Applications
Current Pharmaceutical Biotechnology Xenobiotic Nuclear Receptor-Mediated Regulation of UDP-Glucuronosyltransferases
Current Drug Metabolism New Cell Therapy Using Bone Marrow-Derived Stem Cells/Endothelial Progenitor Cells to Accelerate Neovascularization in Healing of Experimental Ulcerative Colitis
Current Pharmaceutical Design Perspectives of Fullerenes, Dendrimers, and Heterocyclic Compounds Application in Tumor Treatment
Recent Patents on Nanomedicine Content Analysis, Cytotoxic, and Anti-metastasis Potential of Bioactive Polysaccharides from Green Alga <i>Codium intricatum</i> Okamura
Current Bioactive Compounds