Abstract
In the screening of the selective inhibitors of eukaryotic DNA polymerases (pols), dehydroaltenusin was found to be an inhibitor of pol from a fungus (Alternaria tennuis). This compound inhibited only mammalian polα, and did not influence the activities of other replicative pols such as polsαs and Ƹ , but also showed no effect even on polαactivity from another vertebrate, fish, or from a plant species. Dehydroaltenusin also had no influence DNA metabolic enzymes tested. The inhibitory effect of dehydroaltenusin on mammalian polαwas dose-dependent with IC50 value of 0.5 ?M. This effect was 10-fold stronger than that of aphidicolin, a well-known potent eukaryotic polαinhibitor. The inhibitory mode of dehydroaltenusin for mammalian polαactivity was competitive with the DNA template-primer and noncompetitive with the dNTP substrate. We succeeded in chemically synthesizing dehydroaltenusin, and the compound inhibited the cell proliferation of human gastric cancer cell lines by arresting the cells at the S-phase, and preventing the incorporation of thymidine into the cells, indicating that it blocks in vivo DNA replication by inhibiting polα. This compound also induced cell apoptosis. Furthermore, we investigated in vivo anti-tumor effects on nude mice bearing solid tumors of the human cervical cancer cell line HeLa. Dehydroaltenusin was significantly effective in suppressing the growth of solid tumors, therefore, it was of interest as a candidate drug for anti-cancer treatment. These results suggested that dehydroaltenusin is a mammalian polα-specific inhibitor useful in both in vivo and in vitro experiments.
Keywords: Dehydroaltenusin, enzyme inhibitor, DNA polymeraseα, DNA replication, cytotoxicity, cell proliferation, apoptosis, anti-tumor effect
Current Bioactive Compounds
Title: The In Vitro and In Vivo Inhibitory Effect of Dehydroaltenusin: A Specific Inhibitor of Mammalian DNA Polymerase α
Volume: 2 Issue: 1
Author(s): Naoki Maeda, Shinji Kamisuki, Shunya Takahashi, Hiromi Yoshida, Kengo Sakaguchi, Fumio Sugawara and Yoshiyuki Mizushina
Affiliation:
Keywords: Dehydroaltenusin, enzyme inhibitor, DNA polymeraseα, DNA replication, cytotoxicity, cell proliferation, apoptosis, anti-tumor effect
Abstract: In the screening of the selective inhibitors of eukaryotic DNA polymerases (pols), dehydroaltenusin was found to be an inhibitor of pol from a fungus (Alternaria tennuis). This compound inhibited only mammalian polα, and did not influence the activities of other replicative pols such as polsαs and Ƹ , but also showed no effect even on polαactivity from another vertebrate, fish, or from a plant species. Dehydroaltenusin also had no influence DNA metabolic enzymes tested. The inhibitory effect of dehydroaltenusin on mammalian polαwas dose-dependent with IC50 value of 0.5 ?M. This effect was 10-fold stronger than that of aphidicolin, a well-known potent eukaryotic polαinhibitor. The inhibitory mode of dehydroaltenusin for mammalian polαactivity was competitive with the DNA template-primer and noncompetitive with the dNTP substrate. We succeeded in chemically synthesizing dehydroaltenusin, and the compound inhibited the cell proliferation of human gastric cancer cell lines by arresting the cells at the S-phase, and preventing the incorporation of thymidine into the cells, indicating that it blocks in vivo DNA replication by inhibiting polα. This compound also induced cell apoptosis. Furthermore, we investigated in vivo anti-tumor effects on nude mice bearing solid tumors of the human cervical cancer cell line HeLa. Dehydroaltenusin was significantly effective in suppressing the growth of solid tumors, therefore, it was of interest as a candidate drug for anti-cancer treatment. These results suggested that dehydroaltenusin is a mammalian polα-specific inhibitor useful in both in vivo and in vitro experiments.
Export Options
About this article
Cite this article as:
Maeda Naoki, Kamisuki Shinji, Takahashi Shunya, Yoshida Hiromi, Sakaguchi Kengo, Sugawara Fumio and Mizushina Yoshiyuki, The In Vitro and In Vivo Inhibitory Effect of Dehydroaltenusin: A Specific Inhibitor of Mammalian DNA Polymerase α, Current Bioactive Compounds 2006; 2 (1) . https://dx.doi.org/10.2174/1573407210602010003
DOI https://dx.doi.org/10.2174/1573407210602010003 |
Print ISSN 1573-4072 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6646 |

- Author Guidelines
- Bentham Author Support Services (BASS)
- 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
-
Mechanisms of Action of Anesthetics for the Modulation of Perioperative Thrombosis: Evidence for Immune Mechanisms from Basic and Clinical Studies
Current Pharmaceutical Design Defensive and Offensive Cross-Reactive Antibodies Elicited by Pathogens: The Good, the Bad and the Ugly
Current Medicinal Chemistry Low Grade Inflammation as a Common Pathogenetic Denominator in Age-Related Diseases: Novel Drug Targets for Anti-Ageing Strategies and Successful Ageing Achievement
Current Pharmaceutical Design Potassium Channel Blockers and Openers as CNS Neurologic Therapeutic Agents
Recent Patents on CNS Drug Discovery (Discontinued) Mouse Mutants of Relaxin, Insulin-Like 3 Peptide and their Receptors
Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents Editorial: (Thematic Issue Cancer Immunotherapy: Does an Increasing Arsenal of Tools Point to More Fruitful Avenues for Research?)
Anti-Cancer Agents in Medicinal Chemistry Synthesis and Evaluation of Novel Erucin Analogues as Potential Antitumor Compounds
Letters in Organic Chemistry Pentapeptides as Minimal Functional Units in Cell Biology and Immunology
Current Protein & Peptide Science Use of Lactobacilli and their Pheromone-Based Regulatory Mechanism in Gene Expression and Drug Delivery
Current Pharmaceutical Biotechnology The Role of Systemic Treatment and Radiotherapy in Malignant Mesothelioma
Current Respiratory Medicine Reviews Gene Profile Identifies Zinc Transporters Differentially Expressed in Normal Human Organs and Human Pancreatic Cancer
Current Molecular Medicine Recent Innovations in Antibody-Mediated, Targeted Particulate Nanotechnology and Implications for Advanced Visualisation and Drug Delivery
Current Nanoscience Different Aspects of Head and Neck Squamous Cell Carcinoma: Cancer Stem Cells, their Niche and Targeted Therapy
Current Stem Cell Research & Therapy Psychological Sequelae of Ovarian Cancer Screening and Genetic Testing for Ovarian Cancer Susceptibility
Current Women`s Health Reviews HPV as a Model for the Development of Prophylactic and Therapeutic Cancer Vaccines
Current Molecular Medicine Intracellular Bioinorganic Chemistry and Cross Talk Among Different -Omics
Current Topics in Medicinal Chemistry How Similar are Human Mesenchymal Stem Cells Derived from Different Origins? A Review of Comparative Studies
Current Stem Cell Research & Therapy Strategy of Cancer Targeting Gene-Viro-Therapy (CTGVT) a Trend in Both Cancer Gene Therapy and Cancer Virotherapy
Current Pharmaceutical Biotechnology Rheumatoid Foot and Ankle Surgery
Current Rheumatology Reviews Nuclear Magnetic Resonance Spectroscopy of Lipids in Cancer
Current Organic Chemistry