Abstract
Heat shock protein 32 (Hsp32), also known as heme oxygenase 1 (HO-1), has recently been identified as a potential target in various hematologic malignancies. We provide evidence that Hsp32 is constitutively expressed in primary leukemic cells in patients with acute myeloid leukemia (AML) and in various AML cell lines (HL60, U937, KG1). Expression of Hsp32 mRNA was demonstrable by qPCR, and expression of the Hsp32 protein by immunocytochemistry and Western blotting. The stem cell-enriched CD34+/CD38+ and CD34+/CD38- fractions of AML cells were found to express Hsp32 mRNA in excess over normal CD34+ progenitor cells. Two Hsp32-targeting drugs, pegylated zinc-protoporphyrin (PEG-ZnPP) and styrene-maleic-acid-copolymer-micelle-encapsulated ZnPP (SMAZnPP), were found to inhibit cytokine-dependent and spontaneous proliferation in all 3 AML cell lines as well as in primary AML cells. Growth inhibitory effects of SMA-ZnPP and PEG-ZnPP were dose-dependent with IC50 values ranging between 1 and 20 μM, and were accompanied by apoptosis as evidenced by light- and electron microscopy, Tunel assay, and caspase-3 activation. Finally, we were able to demonstrate that SMA-ZnPP inhibits cytokine-dependent proliferation of CD34+/CD38+ and CD34+/CD38- AML progenitor cells in vitro in all patients as well as leukemiainitiation of AML stem cells in NOD-SCID IL-2Rγ-/- (NSG) mice in vivo. Together, our data suggest that Hsp32 plays an important role as a survival factor in leukemic stem cells and as a potential new target in AML.
Keywords: AML, HO-1, Hsp32, survival, targeting, acute myeloid leukemia, allophycocyanin, bone marrow, bovine serum albumin, French-American-British, fetal calf serum, fluorescein isothiocyanate, heme oxygenase-1, heat shock protein 32
Current Cancer Drug Targets
Title: The Hsp32 Inhibitors SMA-ZnPP and PEG-ZnPP Exert Major Growth-Inhibitory Effects on CD34+/CD38+ and CD34+/CD38- AML Progenitor Cells
Volume: 12 Issue: 1
Author(s): H. Herrmann, M. Kneidinger, S. Cerny-Reiterer, T. Rulicke, M. Willmann, K. V. Gleixner, K. Blatt, G. Hormann, B. Peter, P. Samorapoompichit, W. Pickl, G. Y. Bharate, M. Mayerhofer, W. R. Sperr, H. Maeda and P. Valent
Affiliation:
Keywords: AML, HO-1, Hsp32, survival, targeting, acute myeloid leukemia, allophycocyanin, bone marrow, bovine serum albumin, French-American-British, fetal calf serum, fluorescein isothiocyanate, heme oxygenase-1, heat shock protein 32
Abstract: Heat shock protein 32 (Hsp32), also known as heme oxygenase 1 (HO-1), has recently been identified as a potential target in various hematologic malignancies. We provide evidence that Hsp32 is constitutively expressed in primary leukemic cells in patients with acute myeloid leukemia (AML) and in various AML cell lines (HL60, U937, KG1). Expression of Hsp32 mRNA was demonstrable by qPCR, and expression of the Hsp32 protein by immunocytochemistry and Western blotting. The stem cell-enriched CD34+/CD38+ and CD34+/CD38- fractions of AML cells were found to express Hsp32 mRNA in excess over normal CD34+ progenitor cells. Two Hsp32-targeting drugs, pegylated zinc-protoporphyrin (PEG-ZnPP) and styrene-maleic-acid-copolymer-micelle-encapsulated ZnPP (SMAZnPP), were found to inhibit cytokine-dependent and spontaneous proliferation in all 3 AML cell lines as well as in primary AML cells. Growth inhibitory effects of SMA-ZnPP and PEG-ZnPP were dose-dependent with IC50 values ranging between 1 and 20 μM, and were accompanied by apoptosis as evidenced by light- and electron microscopy, Tunel assay, and caspase-3 activation. Finally, we were able to demonstrate that SMA-ZnPP inhibits cytokine-dependent proliferation of CD34+/CD38+ and CD34+/CD38- AML progenitor cells in vitro in all patients as well as leukemiainitiation of AML stem cells in NOD-SCID IL-2Rγ-/- (NSG) mice in vivo. Together, our data suggest that Hsp32 plays an important role as a survival factor in leukemic stem cells and as a potential new target in AML.
Export Options
About this article
Cite this article as:
Herrmann H., Kneidinger M., Cerny-Reiterer S., Rulicke T., Willmann M., V. Gleixner K., Blatt K., Hormann G., Peter B., Samorapoompichit P., Pickl W., Y. Bharate G., Mayerhofer M., R. Sperr W., Maeda H. and Valent P., The Hsp32 Inhibitors SMA-ZnPP and PEG-ZnPP Exert Major Growth-Inhibitory Effects on CD34+/CD38+ and CD34+/CD38- AML Progenitor Cells, Current Cancer Drug Targets 2012; 12 (1) . https://dx.doi.org/10.2174/156800912798888992
DOI https://dx.doi.org/10.2174/156800912798888992 |
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
-
Preferentially Expressed Antigen in Melanoma (PRAME) and the PRAME Family of Leucine-Rich Repeat Proteins
Current Cancer Drug Targets Stem Cell Pharmacogenomics
Current Topics in Medicinal Chemistry Primary Tumors of the Sacrum: Imaging Findings
Current Medical Imaging Promotion of Insulin-Like Growth Factor-I Production by Sensory Neuron Stimulation; Molecular Mechanism(s) and Therapeutic Implications
Current Medicinal Chemistry Editorial (Thematic Issue: Metabolic Disorders, Drug Development, Drug Design and Biomarkers)
Current Pharmaceutical Design TNF-α Inhibitors with Anti-Oxidative Stress Activity from Natural Products
Current Topics in Medicinal Chemistry Biochemical and Pharmacologic Heterogeneity in Low Molecular Weight Heparins. Impact on the Therapeutic Profile
Current Pharmaceutical Design KSP Inhibitors as Antimitotic Agents
Current Topics in Medicinal Chemistry Stem Cell Technologies Based on Hemangioblast Technology Focusing on Human Blood Cells
Recent Patents on Drug Delivery & Formulation Subject Index to Volume 3
Current Medicinal Chemistry - Anti-Cancer Agents Immunomodulatory Activity of Mesenchymal Stem Cells
Current Stem Cell Research & Therapy Nanoparticle-Based Tumor Theranostics with Molecular Imaging
Current Pharmaceutical Biotechnology Bladder Cancer Stem Cells
Current Stem Cell Research & Therapy Boronic Acid Based Inhibitors of Autotaxin: Understanding their Biological Role in Terms of Quantitative Structure Activity Relationships (QSAR)
Letters in Drug Design & Discovery Radionuclide Liver Cancer Therapies: From Concept to Current Clinical Status
Anti-Cancer Agents in Medicinal Chemistry Anti-Angiogenic and Anti-Inflammatory Effects of Statins: Relevance to Anti-Cancer Therapy
Current Cancer Drug Targets Targeting Regulatory T Cells for Anticancer Therapy
Mini-Reviews in Medicinal Chemistry Role of Platelets in Angiogenesis in Health and Disease
Current Angiogenesis (Discontinued) Cinnamic Acid Derivatives as Anticancer Agents-A Review
Current Medicinal Chemistry Apoptosis and Apoptosis-Based Therapy in Lung Cancer
Anti-Cancer Agents in Medicinal Chemistry