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

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Abstract

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.

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Acknowledgments

This work was supported by grants NSC 97-2311-B-006-003-MY3, NSC 97-2323-B-037-001, and NSC 97-2323-B-037-004 from the National Science Council, Taiwan.

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The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Institute of Clinical Medicine, National Cheng Kung University, Medical College, Tainan, Taiwan

    Yu-Peng Liu, Hui-Ling Chen, Pei-Jung Lu & Yu-Cheng Lee

  2. Department of Medicinal and Applied Chemistry, College of Life Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan

    Cherng-Chyi Tzeng, Chih-Hua Tseng & Yeh-Long Chen

  3. Institute of Biotechnology, National University of Kaohsiung, Kaohsiung, Taiwan

    Cheng-Wei Lo & Chia-Ning Yang

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  1. Yu-Peng Liu
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Correspondence to Yeh-Long Chen or Chia-Ning Yang.

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Liu, YP., Chen, HL., Tzeng, CC. et al. TCH-1030 targeting on topoisomerase I induces S-phase arrest, DNA fragmentation, and cell death of breast cancer cells. Breast Cancer Res Treat 138, 383–393 (2013). https://doi.org/10.1007/s10549-013-2441-1

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  • DOI: https://doi.org/10.1007/s10549-013-2441-1

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