Abstract
KP772 is a new lanthanum complex containing three 1,10-phenathroline molecules. Recently, we have demonstrated that the promising in vitro and in vivo anticancer properties of KP772 are based on p53-independent G0/G1 arrest and apoptosis induction. A National Cancer Institute (NCI) screen revealed significant correlation of KP772 activity with that of the ribonucleotide reductase (RR) inhibitor hydroxyurea (HU). Consequently, this study aimed to investigate whether KP772 targets DNA synthesis in tumor cells by RR inhibition. Indeed, KP772 treatment led to significant reduction of cytidine incorporation paralleled by a decrease of deoxynucleoside triphosphate (dNTP) pools. This strongly indicates disruption of RR activity. Moreover, KP772 protected against oxidative stress, suggesting that this drug might interfere with RR by interaction with the tyrosyl radical in subunit R2. Additionally, several observations (e.g. increase of transferrin receptor expression and protective effect of iron preloading) indicate that KP772 interferes with cellular iron homeostasis. Accordingly, co-incubation of Fe(II) with KP772 led to generation of a coloured iron complex (Fe-KP772) in cell free systems. In electron paramagnetic resonance (EPR) measurements of mouse R2 subunits, KP772 disrupted the tyrosyl radical while Fe-KP772 had no significant effects. Moreover, coincubation of KP772 with iron-loaded R2 led to formation of Fe-KP772 suggesting chelation of RR-bound Fe(II). Summarizing, our data prove that KP772 inhibits RR by targeting the iron centre of the R2 subunit. As also Fe-KP772 as well as free lanthanum exert significant -though less pronounced- cytotoxic/static activities, additional mechanisms are likely to synergise with RR inhibition in the promising anticancer activity of KP772.
Keywords: Lanthanum, ribonucleotide reductase, 1,10-phenanthroline, cell cycle arrest, anticancer activity, KP772
Current Cancer Drug Targets
Title: Ribonucleotide Reductase as One Important Target of [Tris(1,10- phenanthroline)lanthanum(III)] Trithiocyanate (KP772)
Volume: 9 Issue: 5
Author(s): P. Heffeter, A. Popovic-Bijelic, P. Saiko, R. Dornetshuber, U. Jungwirth, N. Voevodskaya, D. Biglino, M. A. Jakupec, L. Elbling, M. Micksche, T. Szekeres, B. K. Keppler, A. Graslund and W. Berger
Affiliation:
Keywords: Lanthanum, ribonucleotide reductase, 1,10-phenanthroline, cell cycle arrest, anticancer activity, KP772
Abstract: KP772 is a new lanthanum complex containing three 1,10-phenathroline molecules. Recently, we have demonstrated that the promising in vitro and in vivo anticancer properties of KP772 are based on p53-independent G0/G1 arrest and apoptosis induction. A National Cancer Institute (NCI) screen revealed significant correlation of KP772 activity with that of the ribonucleotide reductase (RR) inhibitor hydroxyurea (HU). Consequently, this study aimed to investigate whether KP772 targets DNA synthesis in tumor cells by RR inhibition. Indeed, KP772 treatment led to significant reduction of cytidine incorporation paralleled by a decrease of deoxynucleoside triphosphate (dNTP) pools. This strongly indicates disruption of RR activity. Moreover, KP772 protected against oxidative stress, suggesting that this drug might interfere with RR by interaction with the tyrosyl radical in subunit R2. Additionally, several observations (e.g. increase of transferrin receptor expression and protective effect of iron preloading) indicate that KP772 interferes with cellular iron homeostasis. Accordingly, co-incubation of Fe(II) with KP772 led to generation of a coloured iron complex (Fe-KP772) in cell free systems. In electron paramagnetic resonance (EPR) measurements of mouse R2 subunits, KP772 disrupted the tyrosyl radical while Fe-KP772 had no significant effects. Moreover, coincubation of KP772 with iron-loaded R2 led to formation of Fe-KP772 suggesting chelation of RR-bound Fe(II). Summarizing, our data prove that KP772 inhibits RR by targeting the iron centre of the R2 subunit. As also Fe-KP772 as well as free lanthanum exert significant -though less pronounced- cytotoxic/static activities, additional mechanisms are likely to synergise with RR inhibition in the promising anticancer activity of KP772.
Export Options
About this article
Cite this article as:
Heffeter P., Popovic-Bijelic A., Saiko P., Dornetshuber R., Jungwirth U., Voevodskaya N., Biglino D., Jakupec A. M., Elbling L., Micksche M., Szekeres T., Keppler K. B., Graslund A. and Berger W., Ribonucleotide Reductase as One Important Target of [Tris(1,10- phenanthroline)lanthanum(III)] Trithiocyanate (KP772), Current Cancer Drug Targets 2009; 9 (5) . https://dx.doi.org/10.2174/156800909789056962
DOI https://dx.doi.org/10.2174/156800909789056962 |
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
-
Nuclear Export as a Novel Therapeutic Target: The CRM1 Connection
Current Cancer Drug Targets Current Developments in the Therapeutic Potential of S-Nitrosoglutathione, an Endogenous NO-Donor Molecule
Current Pharmaceutical Biotechnology Lipoidal-Nano Architecture for Parental Drug Delivery: Formulation Development and Regulatory Concerns
Current Applied Polymer Science Old Tyrosine Kinase Inhibitors and Newcomers in Gastrointestinal Cancer Treatment
Current Cancer Drug Targets BCR-ABL Inhibitors in Chronic Myeloid Leukemia: Process Chemistry and Biochemical Profile
Current Medicinal Chemistry Invasive Aspergillosis: New Insights into Disease, Diagnostic and Treatment
Current Pharmaceutical Design MicroRNAs in Lymphoma: Regulatory Role and Biomarker Potential
Current Genomics <i>In Silico</i> Docking Studies of Vascular Endothelial Growth Factor-A (VEGFA): Possible Implications in Chronic Myeloid Leukemia (CML) Therapy
Current Proteomics Palifermin in theManagement of Mucositis in Hematological Malignancies: Current Evidences and Future Perspectives
Cardiovascular & Hematological Agents in Medicinal Chemistry Cytokine Manipulation of the Immune Response in the Treatment of Human Acute Leukaemia
Current Pharmaceutical Design Can γH2AX be Used to Personalise Cancer Treatment?
Current Molecular Medicine Tyrosine Kinase Inhibitors
Current Cancer Drug Targets Aurora B: A New Prognostic Marker and Therapeutic Target in Cancer
Current Medicinal Chemistry Hck Inhibitors as Potential Therapeutic Agents in Cancer and HIV Infection
Current Medicinal Chemistry Tumor Targeted Therapies: Strategies for Killing Cancer but not Normal Cells
Current Cancer Therapy Reviews Strategies for Overcoming Inherent and Acquired Resistance to EGFR Inhibitors by Targeting Downstream Effectors in the RAS/PI3K Pathway
Current Cancer Drug Targets Tyrosine Kinases as Therapeutic Targets in BCR-ABL Negative Chronic Myeloproliferative Disorders
Current Drug Targets Review of the Contribution of Radiolabelled Tracers for Tumour Cell Status Imaging
Current Medical Imaging Sulfonamides and Sulfonylated Derivatives as Anticancer Agents
Current Cancer Drug Targets DNA Methyltransferase-1 Inhibitors as Epigenetic Therapy for Cancer
Current Cancer Drug Targets