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Front. Pharmacol. | doi: 10.3389/fphar.2018.00411

Extracts of Artocarpus communis induce mitochondria-associated apoptosis via pro-oxidative activity in human glioblastoma cells

 Ming Horng Tsai1*, Chiang-Wen Lee2, Lee-Fen Hsu2, Ming-Hsueh Lee1, I-Ta Lee3,  Ju-Fang Liu4 and  Yao-Chang Chiang5
  • 1Chang Gung Memorial Hospital, Taiwan
  • 2Chang Gung University of Science and Technology, Taiwan
  • 3China Medical University, China
  • 4Shin Kong WHS Memorial Hospital, Taiwan
  • 5China Medical University Hospital, Taiwan

Glioblastoma multiforme (GBM) is an extremely aggressive and devastating malignant tumor in the central nervous system. Its incidence is increasing and the prognosis is poor. Artocarpin is a natural prenylated flavonoid with various anti-inflammatory and anti-tumor properties. Studies have shown that artocarpin is associated with cell death of primary glioblastoma cells. However, the in vivo effects and the cellular and molecular mechanisms modulating the anticancer activities of artocarpin remain unknown. In this study, we demonstrated that treating the glioblastoma cell lines U87 and U118 cells with artocarpin induced apoptosis. Artocarpin-induced apoptosis is associated with caspase activation and poly (ADP-ribose) polymerase (PARP) cleavage and is mediated by the mitochondrial pathway. This is associated with mitochondrial depolarization, mitochondrial-derived reactive oxidative species (ROS) production, cytochrome c release, Bad and Bax upregulations, and Bcl-2 downregulation. Artocarpin induced NADPH oxidase/ROS generation plays an important role in the mitochondrial pathway activation. Furthermore, we found artocarpin-induced ROS production in mitochondria is associated with Akt- and ERK1/2 activation. After treatment with artocarpin, ROS causes PI3K/Akt/ERK1/2-induced cell death of these tumor cells. These observations were further verified by the results from the implantation of both U87 and U118 cells into in vivo mouse. In conclusion, our findings suggest that artocarpin induces mitochondria-associated apoptosis of glioma cells, suggesting that artocarpine can be a potential chemotherapeutic agent for future GBM treatment.

Keywords: Apoptosis, Artocarpin, caspase, Glioblastoma Multiforme, ROS

Received: 15 Sep 2017; Accepted: 09 Apr 2018.

Edited by:

Carine Michiels, Université de Namur, Belgium

Reviewed by:

Nicolas Bidere, Institut National de la Santé et de la Recherche Médicale (INSERM), France
Wen Liang Pan, Beth Israel Deaconess Medical Center, Harvard Medical School, United States  

Copyright: © 2018 Tsai, Lee, Hsu, Lee, Lee, Liu and Chiang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Ming Horng Tsai, Chang Gung Memorial Hospital, No.707, Gongye Rd.,, Sansheng, Mailiao Township, Taipei, 638, Taiwan, mingmin.tw@yahoo.com.tw