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A novel anticancer quinolone, (R)-WAC-224, has anti-leukemia activities against acute myeloid leukemia

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Summary

Approximately 60%–80% of patients who achieve complete remission eventually relapse after conventional chemotherapy and have poor prognoses despite the recent advances of novel anticancer agents. Continuing development of more effective novel treatments for acute myeloid leukemia (AML) is necessary. We developed (R)-WAC-224 (R-WAC), which is an anticancer quinolone, targeting topoisomerase II. This study evaluated the anti-leukemia potential of R-WAC or racemic WAC-224 (WAC) in vitro and in vivo. R-WAC significantly inhibited the human AML cell line proliferation (MV4-11, HL60, and KG1a), which was comparable to daunorubicin and cytarabine, not affected by P-glycoprotein overexpression. WAC did neither increase serum troponin-T nor decrease the crypt numbers in the small intestine, indicating WAC was less toxic than doxorubicin. R-WAC monotherapy demonstrated prolonged survival in the AML mice model and inhibited tumor growth in the MV4-11 xenograft mice model. Moreover, the combination of R-WAC and cytarabine demonstrated more active anti-leukemia effects than daunorubicin and cytarabine. Finally, R-WAC inhibited the colony-forming abilities using primary AML cells. These results indicate that R-WAC is a promising therapeutic agent for AML.

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All can be assessed by contacting the corresponding author (H.U.) and last author (T.Ichinohe).

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Funding

This study was supported by research funds from Wakunaga Pharmaceutical Co. and the Program of the network-type Joint Usage/Research Center for Radiation Disaster Medical Science of Hiroshima University, Nagasaki University, and Fukushima Medical University (to T. Inaba. and T. Ichinohe.).

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Authors and Affiliations

  1. Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Tatsuji Mino, Hiroshi Ureshino & Tatsuo Ichinohe

  2. Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd, Hiroshima, Japan

    Taichi Ueshima, Naoki Kashimoto & Tomonori Yamaguchi

  3. Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Kazuhito Naka

  4. Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Toshiya Inaba

Authors
  1. Tatsuji Mino
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  2. Hiroshi Ureshino
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  3. Taichi Ueshima
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  4. Naoki Kashimoto
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  5. Tomonori Yamaguchi
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  6. Kazuhito Naka
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  7. Toshiya Inaba
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  8. Tatsuo Ichinohe
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Contributions

T.M., H.U., T.U., N.K., T.Y. and T.Ichinohe designed, and T.M. and T.U. conducted most experiments; T.U., N.K., T.Y contributed to animal experiments; M.T., K.N. and T.Inaba. performed colony-formation assay; T.M, H.U. and T.U. performed statistical analyses; T.M., H.U., U.T and T. Ichinohe wrote the manuscript, and all authors approved the final version.

Corresponding author

Correspondence to Hiroshi Ureshino.

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Conflict of interest disclosure

This work was supported by research funds from Wakunaga Pharmaceutical Co., Ltd. T.I. has received research funds from Wakunaga Pharmaceutical Co., Ltd. T.U., NK and T.Y. are full-time employees of Wakunaga Pharmaceutical Co., Ltd. No other authors have relevant conflict-of-interest to declare.

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Supplementary file2 Table S1. IC50 in acute myeloid leukemia cell lines and normal human lung fibroblast cell (μM). (PDF 81 KB)

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Mino, T., Ureshino, H., Ueshima, T. et al. A novel anticancer quinolone, (R)-WAC-224, has anti-leukemia activities against acute myeloid leukemia. Invest New Drugs 41, 751–760 (2023). https://doi.org/10.1007/s10637-023-01393-0

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