TCH-1030 targeting on topoisomerase I induces S-phase arrest, DNA fragmentation, and cell death of breast cancer cells
| Autor: | Chia-Ning Yang, Yeh-Long Chen, Cheng-Wei Lo, Hui Ling Chen, Yu-Peng Liu, Chih-Hua Tseng, Cherng-Chyi Tzeng, Yu-Cheng Lee, Pei Jung Lu |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Cancer Research DNA damage Antineoplastic Agents Apoptosis Breast Neoplasms DNA Fragmentation chemistry.chemical_compound Inhibitory Concentration 50 Mice Catalytic Domain Cell Line Tumor Oximes medicine Animals Humans Molecular Targeted Therapy biology Topoisomerase Cell cycle Molecular biology Xenograft Model Antitumor Assays Tumor Burden Oncology chemistry Mechanism of action DNA Topoisomerases Type I S Phase Cell Cycle Checkpoints biology.protein Quinolines DNA fragmentation Camptothecin Female medicine.symptom Topoisomerase I Inhibitors DNA medicine.drug |
| Zdroj: | Breast cancer research and treatment. 138(2) |
| ISSN: | 1573-7217 |
| Popis: | Camptothecin (CPT) and its derivatives are powerful anticancer agents, but these compounds are chemically unstable due to their α-hydroxy lactone six-membered E-ring structure, which is essential for trapping topoisomerase I (topo I)-DNA cleavage complexes. Moreover, the reversibility of trapping the topo I-DNA cleavage complex and the tight binding of CPTs to human serum albumin limit the levels of available active drug. CPT analogs are the only clinically available drugs that target topo I. Owing to the clinical importance of CPT analogs, the development of new anticancer agents which inhibit topo I is urgently needed. In the present study, we report the synthesis, biologic evaluation, and molecular mechanism of a series of substituted indeno[1,2-c]quinoline derivatives against the growth of several human cancer cell lines. We found that 9-methoxy-6-(piperazin-1-yl)-11H-indeno[1,2-c]quinoline-11-one O-3-(dimethylamino)propyl oxime (TCH-1030) intercalated into DNA and preferentially inhibited DNA topo I relaxation. Flow cytometric analysis and BrdU incorporation assays indicate that TCH-1030 alters cell cycle progression, induces S-phase arrest, and causes DNA polyploidy (>4 N) that is distinct from the typical G2-M arrest reported with known topoisomerase toxins. Our data indicate that TCH-1030 induces caspase 3 activation, PARP cleavage, γ-H2AX phosphorylation, and, consequently, DNA fragmentation and apoptosis. We also demonstrated that treatment with TCH-1030 significantly inhibits tumor growth in a BT483-xenograft nude mouse model. Taken together, we conclude that the primary mechanism of action of TCH-1030-induced cell cycle retardation and apoptosis-mediated DNA damage involves DNA binding and intercalation as well as topo I inhibition. |
| Databáze: | OpenAIRE |
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