Abstract
ATP-binding cassette (ABC) transporters are a super family of channel proteins that include multidrug resistance 1 (MDR1/P-gp) and multi-drug resistance related proteins (MRPs) whose functions include the efflux of ions, nutrients, lipids, amino acids, peptides, proteins and drugs. The three-dimensional structures of bacterial and human ABC transporters demonstrate that these proteins are ATP-dependent molecular machines that scan the inner membrane leaflet for lipids/drugs and flip them to the outer membrane leaflet. In many human cancers, the level of expression of MDR1 is an important independent prognostic factor that determines response to combination chemotherapy. Intrinsic and acquired resistance to chemotherapy exposure are due to a high level of MDR1 expression that enhances drug efflux, with associated poor clinical outcome and lower complete remission (CR) rates. Recent clinical trials in hematological and solid malignancies have shown promise for a prolonged remission and improved overall survival when the MDR1 P-gp is inhibited when combined with chemotherapy. Structure-based homology modeling of these ABC transporters may help design novel drug candidates to both the membrane-spanning domain (MSD) and the nucleotide-binding domain (NBD) located within the cytoplasm. This review will highlight advances in the utilization of homology modeling in the drug discovery process and how this will impact on fundamental insights to the development of novel therapeutics that could alter and/or inhibit their functions.
Keywords: mdr/p-gp, cancer, modeling, docking, pharmacology
Current Cancer Drug Targets
Title: Strategies for Targeting the Multidrug Resistance-1 (MDR1)/P-gp Transporter in Human Malignancies
Volume: 5 Issue: 6
Author(s): Daruka Mahadevan and Nikhil Shirahatti
Affiliation:
Keywords: mdr/p-gp, cancer, modeling, docking, pharmacology
Abstract: ATP-binding cassette (ABC) transporters are a super family of channel proteins that include multidrug resistance 1 (MDR1/P-gp) and multi-drug resistance related proteins (MRPs) whose functions include the efflux of ions, nutrients, lipids, amino acids, peptides, proteins and drugs. The three-dimensional structures of bacterial and human ABC transporters demonstrate that these proteins are ATP-dependent molecular machines that scan the inner membrane leaflet for lipids/drugs and flip them to the outer membrane leaflet. In many human cancers, the level of expression of MDR1 is an important independent prognostic factor that determines response to combination chemotherapy. Intrinsic and acquired resistance to chemotherapy exposure are due to a high level of MDR1 expression that enhances drug efflux, with associated poor clinical outcome and lower complete remission (CR) rates. Recent clinical trials in hematological and solid malignancies have shown promise for a prolonged remission and improved overall survival when the MDR1 P-gp is inhibited when combined with chemotherapy. Structure-based homology modeling of these ABC transporters may help design novel drug candidates to both the membrane-spanning domain (MSD) and the nucleotide-binding domain (NBD) located within the cytoplasm. This review will highlight advances in the utilization of homology modeling in the drug discovery process and how this will impact on fundamental insights to the development of novel therapeutics that could alter and/or inhibit their functions.
Export Options
About this article
Cite this article as:
Mahadevan Daruka and Shirahatti Nikhil, Strategies for Targeting the Multidrug Resistance-1 (MDR1)/P-gp Transporter in Human Malignancies, Current Cancer Drug Targets 2005; 5 (6) . https://dx.doi.org/10.2174/1568009054863609
DOI https://dx.doi.org/10.2174/1568009054863609 |
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
-
Advances in Oncolytic Virus Therapy for Glioma
Recent Patents on CNS Drug Discovery (Discontinued) Observations of the Mechanisms of Electromediated DNA Uptake - From Vesicles to Tissues
Current Gene Therapy Transition Metal-Based Prodrugs for Anticancer Drug Delivery
Current Medicinal Chemistry Diselenides and Selenocyanates as Versatile Precursors for the Synthesis of Pharmaceutically Relevant Compounds
Current Organic Synthesis Polymorphism in Endothelin-1 Gene: An Overview
Current Clinical Pharmacology Laminin and Collagen IV: Two Polypeptides as Marker of Dystocic Labor
Current Protein & Peptide Science An Overview on the Development of New Potentially Active Camptothecin Analogs Against Cancer
Mini-Reviews in Medicinal Chemistry Antidiabetic Drugs: Mechanisms of Action and Potential Outcomes on Cellular Metabolism
Current Pharmaceutical Design Computer-Aided Drug Design for Cancer-Causing H-Ras p21 Mutant Protein
Letters in Drug Design & Discovery Vascular Endothelial Growth Factor as an Anti-Angiogenic Target for Cancer Therapy
Current Drug Targets Antitumor Activity of Cyclodextrin-based Supramolecular Platinum Prodrug In vitro and In vivo
Letters in Drug Design & Discovery GLP-1RA and SGLT2i: Cardiovascular Impact on Diabetic Patients
Current Hypertension Reviews New Approaches in Glioblastoma Multiforme: The Potential Role of Immune- check Point Inhibitors
Current Cancer Drug Targets Hypoxia Responsive Drug Delivery Systems in Tumor Therapy
Current Pharmaceutical Design Beyond Cox-Inhibition: ‘Side-Effects’ of Ibuprofen on Neoplastic Development and Progression
Current Pharmaceutical Design Expression and Characterisation of Recombinant Molecules in Transgenic Soybean
Current Pharmaceutical Design Pore-forming Peptides: A New Treatment Option for Cancer
Current Medicinal Chemistry A Brief Evaluation of Tumor Imaging in Mice with 99mTc-glucarate Including a Comparison with 18F-FDG
Current Radiopharmaceuticals Cancer T Cell Immunotherapy with Bispecific Antibodies and Chimeric Antigen Receptors
Recent Patents on Anti-Cancer Drug Discovery Image-Guided Drug Delivery with Single-Photon Emission Computed Tomography: A Review of Literature
Current Drug Targets