Oncotarget

Research Papers:

Traditional Chinese medicine Danggui Buxue Tang inhibits colorectal cancer growth through induction of autophagic cell death

Shun-Ting Chen, Tzung-Yan Lee, Tung-Hu Tsai, Yu-Chuen Huang, Yin-Cheng Lin, Chin-Ping Lin, Hui-Ru Shieh, Ming-Ling Hsu, Chih-Wen Chi, Ming-Cheng Lee, Hen-Hong Chang and Yu-Jen Chen _

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Oncotarget. 2017; 8:88563-88574. https://doi.org/10.18632/oncotarget.19902

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Abstract

Shun-Ting Chen1,2,3, Tzung-Yan Lee2, Tung-Hu Tsai4,12, Yu-Chuen Huang5,6, Yin-Cheng Lin7, Chin-Ping Lin7, Hui-Ru Shieh7, Ming-Ling Hsu7, Chih-Wen Chi7, Ming-Cheng Lee8, Hen-Hong Chang9,10 and Yu-Jen Chen6,7,11

1Department of Chinese Medicine, Taipei Buddhist Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan

2Graduate Institute of Traditional Chinese Medicine, School of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan

3Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan

4Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan

5School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan

6Department of Medical Research, China Medical University Hospital, Taichung 40402, Taiwan

7Department of Medical Research, Mackay Memorial Hospital, New Taipei City 25160, Taiwan

8Department of Research, Taipei Buddhist Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23141, Taiwan

9School of Post-Baccalaureate Chinese Medicine, College of Chinese Medicine, and Research Center for Chinese Medicine and Acupuncture, China Medical University, Taichung 40402, Taiwan

10Department of Chinese Medicine, China Medical University Hospital, Taichung 40402, Taiwan

11Department of Radiation Oncology, Mackay Memorial Hospital, Taipei 10449, Taiwan

12Depatment of Chemical Engineering, National United University, Miaoli 36003, Taiwan

Correspondence to:

Yu-Jen Chen, email: chenmdphd@gmail.com

Hen-Hong Chang, email: tcmchh55@mail.cmu.edu.tw

Keywords: Danggui Buxue Tang, colorectal cancer, autophagy, traditional Chinese medicine, mammalian target of rapamycin (mTOR)

Received: February 03, 2017     Accepted: July 12, 2017     Published: August 03, 2017

ABSTRACT

Purpose: The induction of autophagic cell death is an important process in the development of anticancer therapeutics. We aimed to evaluate the activity of the ancient Chinese decoction Danggui Buxue Tang (DBT) against colorectal cancer (CRC) and the associated autophagy-related mechanism.

Materials and methods: CT26 CRC cells were implanted into syngeneic BALB/c mice for the tumor growth assay. DBT extracts and DBT-PD (polysaccharide-depleted) fractions were orally administered. The toxicity profiles of the extracts were analyzed using measurements of body weight, hemogram, and biochemical parameters. The morphology of tissue sections was observed using light and transmission electron microscopy. Western blotting and small interference RNA assays were used to determine the mechanism.

Results: DBT-PD and DBT, which contained an equal amount of DBT-PD, inhibited CT26 syngeneic tumor growth. In the tumor specimen, the expression of microtubule-associated proteins 1A/1B light chain 3B (LC3B) was upregulated by DBT-PD and DBT. The development of autophagosomes was observed via transmission electron microscopy in tumors treated with DBT-PD and DBT. In vitro experiments for mechanism clarification demonstrated that DBT-PD could induce autophagic death in CT26 cells accompanied by LC3B lipidation, downregulation of phospho-p70s6k, and upregulation of Atg7. RNA interference of Atg7, but not Atg5, partially reversed the effect of DBT-PD on LC3B lipidation and expression of phospho-p70s6k and Atg7. The changes in ultrastructural morphology and LC3B expression induced by DBT-PD were also partially blocked by the knockdown of Atg7 mRNA.

Conclusion: DBT induced autophagic death of colorectal cancer cells through the upregulation of Atg7 and modulation of the mTOR/p70s6k signaling pathway.


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