Abstract
Heme is the functional group of diverse hemoproteins and crucial for many cellular processes. However, heme is increasingly recognized as a culprit for a wide variety of pathologies, including sepsis, malaria, and kidney failure. Excess of free heme can be detrimental to tissues by mediating oxidative and inflammatory injury. Protective mechanisms against free heme are therefore pivotal for cellular survival. We postulated that overexpression of Heme Oxygenase-1 (HO-1) and Breast Cancer Resistance Protein (BCRP) would protect against heme-induced cytotoxicity. HO-1 is a heme-degrading enzyme generating carbon monoxide, iron, and biliverdin/bilirubin, while BCRP is a heme efflux transporter. Human embryonic kidney cells were transduced using a baculovirus system as a novel strategy to efficiently overexpress HO-1 and BCRP. Exposing cells to heme resulted in a dose-dependent increase in reactive oxygen species formation, DNA damage and cell death. Heme-induced cell death was significantly attenuated when cells overexpressed HO-1, BCRP, or both. The protective effects of HO-1 overexpression were most pronounced, while co-treatment with the HO-activity inhibitor tin mesoporphyrin reversed these protective effects. Also cells treated with the anti-oxidants N-acetylcysteine or HO-effector molecule bilirubin showed protection against heme insults, which may explain the increased protection by HO-1 compared to BCRP. In conclusion, both HO-1 and BCRP protect against heme-induced toxicity and may thus form novel therapeutic targets for heme-mediated pathologies.
Keywords: Heme-HO system, ABC transporter, ABCG2, BCRP, cytotoxicity, reactive oxygen species, DNA damage, redox balance
Current Pharmaceutical Design
Title:Heme Oxygenase-1 and Breast Cancer Resistance Protein Protect Against Hemeinduced Toxicity
Volume: 19 Issue: 15
Author(s): Frank A.D.T.G. Wagener, Anita C.A. Dankers, Frank van Summeren, Alwin Scharstuhl, Jeroen J.M.W. van den Heuvel, Jan B. Koenderink, Sebastiaan W.C. Pennings, Frans G.M. Russel and Rosalinde Masereeuw
Affiliation:
Keywords: Heme-HO system, ABC transporter, ABCG2, BCRP, cytotoxicity, reactive oxygen species, DNA damage, redox balance
Abstract: Heme is the functional group of diverse hemoproteins and crucial for many cellular processes. However, heme is increasingly recognized as a culprit for a wide variety of pathologies, including sepsis, malaria, and kidney failure. Excess of free heme can be detrimental to tissues by mediating oxidative and inflammatory injury. Protective mechanisms against free heme are therefore pivotal for cellular survival. We postulated that overexpression of Heme Oxygenase-1 (HO-1) and Breast Cancer Resistance Protein (BCRP) would protect against heme-induced cytotoxicity. HO-1 is a heme-degrading enzyme generating carbon monoxide, iron, and biliverdin/bilirubin, while BCRP is a heme efflux transporter. Human embryonic kidney cells were transduced using a baculovirus system as a novel strategy to efficiently overexpress HO-1 and BCRP. Exposing cells to heme resulted in a dose-dependent increase in reactive oxygen species formation, DNA damage and cell death. Heme-induced cell death was significantly attenuated when cells overexpressed HO-1, BCRP, or both. The protective effects of HO-1 overexpression were most pronounced, while co-treatment with the HO-activity inhibitor tin mesoporphyrin reversed these protective effects. Also cells treated with the anti-oxidants N-acetylcysteine or HO-effector molecule bilirubin showed protection against heme insults, which may explain the increased protection by HO-1 compared to BCRP. In conclusion, both HO-1 and BCRP protect against heme-induced toxicity and may thus form novel therapeutic targets for heme-mediated pathologies.
Export Options
About this article
Cite this article as:
A.D.T.G. Wagener Frank, C.A. Dankers Anita, van Summeren Frank, Scharstuhl Alwin, J.M.W. van den Heuvel Jeroen, B. Koenderink Jan, W.C. Pennings Sebastiaan, G.M. Russel Frans and Masereeuw Rosalinde, Heme Oxygenase-1 and Breast Cancer Resistance Protein Protect Against Hemeinduced Toxicity, Current Pharmaceutical Design 2013; 19 (15) . https://dx.doi.org/10.2174/1381612811319150004
DOI https://dx.doi.org/10.2174/1381612811319150004 |
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
-
Implication of CD154/CD40 Interaction in Healthy and Autoimmune Responses
Current Immunology Reviews (Discontinued) Targeted Lipid Nanoparticles for Antisense Oligonucleotide Delivery
Current Pharmaceutical Biotechnology Role of Muscarinic Acetylcholine Receptors in Breast Cancer: Design of Metronomic Chemotherapy
Current Clinical Pharmacology Cell Hierarchy, Metabolic Flexibility and Systems Approaches to Cancer Treatment
Current Pharmaceutical Biotechnology Phosphonium Salt Displays Cytotoxic Effects Against Human Cancer Cell Lines
Anti-Cancer Agents in Medicinal Chemistry Drug Metabolism and Pharmacokinetics of Nanodrugs from Chinese Medicines and Natural Products
Current Drug Metabolism Molecular Pathways of Endothelial Cell Activation for (Targeted) Pharmacological Intervention of Chronic Inflammatory Diseases
Current Vascular Pharmacology Targeting the Nogo-A Signalling Pathway to Promote Recovery Following Acute CNS Injury
Current Pharmaceutical Design Function and Regulation of Let-7 Family microRNAs
MicroRNA Antibody-directed Double Suicide Gene Therapy Targeting of MUC1- Positive Leukemia Cells In Vitro and In Vivo
Current Gene Therapy The Role of Fatty Acids in the Activity of the Uncoupling Proteins
Current Chemical Biology Mast Cells as Target in Cancer Therapy
Current Pharmaceutical Design Polyphenols Counteract Tumor Cell Chemoresistance Conferred by Multidrug Resistance Proteins
Anti-Cancer Agents in Medicinal Chemistry A Pharmacokinetic-Pharmacodynamic Model of Tamoxifen and Endoxifen to Predict Their Distribution and Effects on Inhibition of Tumor Growth
Drug Metabolism Letters The Effect of Drugs on the Labeling of Blood Elements with Technetium-99m
Current Pharmaceutical Design Cytotoxic Effect of the Combination of Gemcitabine and Atorvastatin Loaded in Nanoparticle on the MCF-7 Breast Cancer Cells and HFS Human Foreskin Cells
Current Nanoscience Bacterial Translocation, Microcirculation Injury and Sepsis
Endocrine, Metabolic & Immune Disorders - Drug Targets Thermal N-9 → N-7 Isomerization of (6-Substituted)-9-(2,3-Dihydro-5H-1,4-Benzodioxepin-3-yl)-9H-Purines in Solution: Mechanistic Aspects
Mini-Reviews in Organic Chemistry Ionic Liquid Mediated Synthesis of Novel tetrahydroimidazo [1,2- a]pyrimidine-6-carboxylate Derivatives
Letters in Organic Chemistry The Molecular Functions of Nod Proteins and their Associated Diseases
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents