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Alantolactone induces apoptosis in chronic myelogenous leukemia sensitive or resistant to imatinib through NF-κB inhibition and Bcr/Abl protein deletion

Apoptosis volume 18, pages 1060–1070 (2013)Cite this article

Abstract

Alantolactone, an allergenic sesquiterpene lactone, has recently been found to have significant antitumor effects on malignant tumor cells. Here, we investigated the potential effect of alantolactone on Bcr/Abl+ imatinib-sensitive and -resistant cells. Alantolactone treatment resulted in obvious apoptosis in both imatinib-sensitive and -resistant K562 cells, as shown by the increase in Annexin V-positive cells, caspase-3 activation, poly(ADP-ribose) polymerase-1 (PARP-1) cleavage and mitochondrial membrane potential collapse. Alantolactone significantly inhibited NF-κB-dependent reporter gene activity, decreased the DNA-binding activity of NF-ОκB, and blocked TNF-α-induced IκBα phosphorylation. Of interest, the oncogenic Bcr/Abl fusion protein but not its mRNA levels were quickly reduced upon alantolactone exposure in imatinib-sensitive and -resistant K562 cells. Bcr/Abl knockdown enhanced the apoptosis driven by alantolactone. Bcr/Abl protein reduction could not be reversed by the addition of proteasome or caspase-3 inhibitors. The overexpression of p65 inhibited alantolactone-induced apoptosis, whereas p65 or Bcr/Abl silencing enhanced its apoptotic-inducing effect. Furthermore, Bcr/Abl-transfected 32D cells showed more sensitivity to alantolactone than vector-transfected control cells, and the Bcr/Abl protein was depleted, as observed in K562 cells. Finally, alantolactone-induced apoptosis was also observed in primary CD34+ CML leukemic cells. Collectively, these findings suggest that alantolactone is a promising potent agent to fight against CML cells via the inhibition of the NF-κB signaling pathway and depletion of the Bcr/Abl protein.

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Acknowledgments

This work was supported in part by the National Basic Research Program of China (973 Program) (NO. 2010CB912104); National Natural Science Foundation (81170509, 81070433, 91013008, 81272886, 30570777); Science and Technology Committee of Shanghai (11JC1406500); SMC Program of Shanghai Jiao Tong University. We thank Dr Melo JV for her kindly provided the K562 and K562r cells.

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The authors declare no conflict of interest.

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Affiliations

  1. Department of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, No. 197, Ruijin Er Road, Shanghai, 200025, China

    Wei Wei, He Huang, Li Chen, Jun-Min Li & Hua Yan

  2. Department of Pathophysiology, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao-Tong University School of Medicine, No. 280, Chongqing South Road, Shanghai, 200025, China

    Shan Zhao, Wei Liu, Chuan-Xu Liu & Ying-Li Wu

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  1. Wei Wei
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  2. He Huang
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  9. Hua Yan
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Correspondence to Ying-Li Wu or Hua Yan.

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Wei Wei and He Huang contributed equally to this study.

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Wei, W., Huang, H., Zhao, S. et al. Alantolactone induces apoptosis in chronic myelogenous leukemia sensitive or resistant to imatinib through NF-κB inhibition and Bcr/Abl protein deletion. Apoptosis 18, 1060–1070 (2013). https://doi.org/10.1007/s10495-013-0854-2

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Keywords

  • Alantolactone
  • Chronic myelogenous leukemia
  • Apoptosis
  • Bcr/Abl
  • NF-κB