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Nobiletin suppresses the proliferation and induces apoptosis involving MAPKs and caspase-8/-9/-3 signals in human acute myeloid leukemia cells

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Tumor Biology

Abstract

Nobiletin, a compound isolated from citrus fruits, is a polymethoxylated flavone derivative that was shown to have anti-inflammatory and anticancer activities in various solid tumors. The anticancer effect of nobiletin on nonsolid tumor remains unclear. Herein, the molecular mechanisms by which nobiletin exerts its anticancer effects on acute myeloid leukemia (AML) cells were investigated. The results showed that nobiletin suppressed cell proliferation in various types of AML cell lines. Moreover, nobiletin induced cell-cycle arrest of HL-60 AML cells at the G0/G1 phase by suppressing extracellular signal-regulated kinase (ERK) activity. Furthermore, nobiletin effectively induced apoptosis of HL-60 cells through caspase-8, caspase-9, and caspases-3 activation concomitantly with a marked induction of p38 mitogen-activated protein kinase (MAPK) activation, but without affecting expression levels of Bcl-2, Bax, or Bid. Taken together, our results suggest that nobiletin inhibited HL-60 cell proliferation through inducing cell-cycle arrest and apoptosis and could serve as a potential additional chemotherapeutic agent for treating AML.

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Acknowledgments

This work was supported by a research grant (no. 103 swf03) from Taipei Medical University-Wan Fang Hospital and a grant (TAFGH-103-29) from Taoyuan Armed Forces General Hospital and also supported by a grant (CSH-2014-C-020) from Chung Shan Medical University Hospital.

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Authors and Affiliations

  1. School of Medicine, Chung Shan Medical University, Taichung, Taiwan

    Pei-Ching Hsiao

  2. Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan

    Pei-Ching Hsiao

  3. Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    Wei-Jiunn Lee & Liang-Ming Lee

  4. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan

    Shun-Fa Yang & Hui-Yu Chen

  5. Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan

    Shun-Fa Yang

  6. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan

    Peng Tan & Ming-Hsien Chien

  7. Department of Medical Management, Taoyuan Armed Forces General Hospital, Taoyuan County, Taiwan

    Junn-Liang Chang

  8. School of Medicine, Pathology Department, National Defense Medical Center, Taipei, Taiwan

    Junn-Liang Chang

  9. Biomedical Engineering Department, Ming Chuan University, Taoyuan County, Taiwan

    Junn-Liang Chang

  10. Division of Hematology and Medical Oncology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, 111 Hsing Long Road, Section 3, Taipei 116, Taiwan

    Gi-Ming Lai & Jyh-Ming Chow

  11. Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    Gi-Ming Lai

  12. Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    Ming-Hsien Chien

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  1. Pei-Ching Hsiao
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  2. Wei-Jiunn Lee
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  4. Peng Tan
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  7. Junn-Liang Chang
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  8. Gi-Ming Lai
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  9. Jyh-Ming Chow
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  10. Ming-Hsien Chien
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Correspondence to Jyh-Ming Chow or Ming-Hsien Chien.

Additional information

Pei-Ching Hsiao and Wei-Jiunn Lee contributed equally to this work.

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Hsiao, PC., Lee, WJ., Yang, SF. et al. Nobiletin suppresses the proliferation and induces apoptosis involving MAPKs and caspase-8/-9/-3 signals in human acute myeloid leukemia cells. Tumor Biol. 35, 11903–11911 (2014). https://doi.org/10.1007/s13277-014-2457-0

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  • DOI: https://doi.org/10.1007/s13277-014-2457-0

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