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Apoptosis induction by alantolactone in breast cancer MDA-MB-231 cells through reactive oxygen species-mediated mitochondrion-dependent pathway

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Abstract

Alantolactone is a sesquiterpene lactone isolated from Inula helenium L. Although alantolactone possesses anti-inflammation and apoptosis-induction activities, the underlying mechanism of anti-cancer effect on human breast cancer cells remains largely unknown. In this study, we explored the possibility of alantolactone as an apoptosis-inducing cytotoxic agent using MDA-MB-231 cells as in vitro model. Alantolactone significantly induced its apoptosis, demonstrated by cell cycle analysis, annexin V-APC/7-AAD double staining and dUTP nick end labeling. Additionally, alantolactone triggered the mitochondrial-mediated caspase cascade apoptotic pathway, which was confirmed by increased Bax/Bcl-2 ratio, loss of MMP, release of cytc from mitochondria to cytoplasm, activation of caspase 9/3, and subsequent cleavage of PARP. Z-VAD-FMK partially prevented apoptosis induced by alantolactone. Alantolactone provoked the production of ROS, while NAC (a scavenger of ROS) reversed alantolactone-mediated depolarization of MMP and apoptosis. Alantolactone modulated the activities of MAPKs. As expected, cotreatment with SB203580, SP600125 or U0126 could reduced the apoptotic rate. Furthermore, alantolactone decreased the protein expressions of p-NF-kB p65 and p-STAT3, increased p-c-Jun level in a dose-dependent manner. These findings suggested that alantolactone possessed anticancer activity via ROS-mediated mitochondrial dysfunction involving MAPK pathway, and had an effect on the transcription factors of NF-kB, AP-1 and STAT3.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81403121 and 81503306), Young Medical Talent Project of Jiangsu Province (QNRC2016636) and the Natural Science Foundation of Jiangsu Province (BK20151045).

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Authors and Affiliations

  1. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 210028, Nanjing, China

    Li Cui, Tingting Xu, Dan Liu, Wenbo Ding, Jianhua Wang, Changyang Li, Binge Ma, Yi Luo, Ziyu Jiang & Xiaobin Jia

  2. Key Laboratory of New Drug Delivery System of Chinese Meteria Medica, Jiangsu Province Academy of Chinese Medicine, 210028, Nanjing, China

    Li Cui, Weiquan Bu, Jie Song, Liang Feng, Chengcheng Wang, Juan Chen, Jian Hou, Hongmei Yan, Lei Yang & Xiaobin Jia

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  1. Li Cui
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  3. Jie Song
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Cui, L., Bu, W., Song, J. et al. Apoptosis induction by alantolactone in breast cancer MDA-MB-231 cells through reactive oxygen species-mediated mitochondrion-dependent pathway. Arch. Pharm. Res. 41, 299–313 (2018). https://doi.org/10.1007/s12272-017-0990-2

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