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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

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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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Authors and 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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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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