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Longikaurin E induces apoptosis of pancreatic cancer cells via modulation of the p38 and PI3K/AKT pathways by ROS

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Abstract

Pancreatic cancer is a devastating disease with a poor prognosis. It ranks as the fourth or fifth most common cancer in men and women and has the lowest 5-year survival rate. Therefore, there is an urgent need to develop novel therapeutic agents for pancreatic cancer. Longikaurin E (LE), which is derived from the traditional herbal medicine Rabdosia longituba, had been reported to have anti-proliferative and pro-apoptotic properties in several types of cancers. In this study, we investigated the cytotoxic properties of LE against pancreatic cancer cells and explored the mechanism behind the observed apoptosis. Pancreatic cancer cell lines cultured in the presence of LE exhibited dose- and time-dependent growth suppression by clone formation, methylthiazoltetrazolium assay, lactate dehydrogenase cytotoxicity assay, and fluorescence-activated cell sorting analysis, respectively. In addition, these culture conditions also induced the generation of cellular reactive oxygen species (ROS). In order to determine the mechanisms underlying LE-induced cytotoxicity, we used reverse transcription polymerase chain reaction and Western blot analysis in the pancreatic cancer cell line PANC1. The results showed that the expression of Bax was noticeably upregulated and the expression levels of Bcl-2, Bcl-XL, survivin, and c-Myc were significantly downregulated. We also observed increased p38 phosphorylation and decreased phosphorylation of the PI3K/AKT pathway. Interestingly, we also found that LE activated caspase-3. However, N-acetyl-l-cysteine, a kind of antioxidant, reversed all of these cellular activities. In conclusion, this study suggested that LE induced apoptosis of pancreatic cancer cells via ROS generation to modulate the p38 and PI3K/AKT pathways and could be a promising anti-pancreatic agent.

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Authors and Affiliations

  1. Translational Medicine Research Center, Nanjing University of Chinese Medicine, No. 138, Xianlin Road, Nanjing, Jiangsu, People’s Republic of China

    Hai-bo Cheng, Wei-xing Shen, Jia-ni Tan, Zhi-rong Jia & Chang-Liang Xu

  2. Key Laboratory of SATCM for Empirical Formulae Evaluation and Achievements Transformation, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China

    Hai-bo Cheng, Wei-xing Shen, Jia-ni Tan, Zhi-rong Jia & Chang-Liang Xu

  3. Jiangsu Provincial Laboratory of Tumor-Resistant Empirical Formulae Evaluation and Industrialization, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China

    Hai-bo Cheng, Wei-xing Shen, Jia-ni Tan, Zhi-rong Jia & Chang-Liang Xu

  4. Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China

    Yun Bo

  5. Department of Pediatric Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, People’s Republic of China

    Xian-guo Ren

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  1. Hai-bo Cheng
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Cheng, Hb., Bo, Y., Shen, Wx. et al. Longikaurin E induces apoptosis of pancreatic cancer cells via modulation of the p38 and PI3K/AKT pathways by ROS. Naunyn-Schmiedeberg's Arch Pharmacol 388, 623–634 (2015). https://doi.org/10.1007/s00210-015-1107-4

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