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

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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Correspondence to Jyh-Ming Chow or Ming-Hsien Chien.

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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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Keywords

  • Nobiletin
  • Apoptosis
  • G0/G1 arrest
  • Acute myeloid leukemia