TCH-1030 targeting on topoisomerase i induces S-phase arrest, DNA fragmentation, and cell death of breast cancer cells

Yu Peng Liu, Hui Ling Chen, Cherng Chyi Tzeng, Pei Jung Lu, Cheng Wei Lo, Yu Cheng Lee, Chih Hua Tseng, Yeh Long Chen, Chia Ning Yang

研究成果: Article同行評審

10 引文 斯高帕斯(Scopus)

摘要

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.

原文English
頁(從 - 到)383-393
頁數11
期刊Breast Cancer Research and Treatment
138
發行號2
DOIs
出版狀態Published - 2013 四月

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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