DangGui BuXue Tang Sensitizes Colorectal Cancer Cells to Chemoradiotherapy in vitro and in vivo Model
博士 === 長庚大學 === 臨床醫學研究所中醫組 === 105 === Chemotherapy is an important treatment modality for colon cancer, and concurrent chemoradiation therapy (CCRT) is the preferred treatment route for patients with stage II and III rectal cancer. The induction of autophagic cell death is an important process in t...
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ndltd-TW-105CGU055210302019-06-27T05:27:21Z http://ndltd.ncl.edu.tw/handle/2469ah DangGui BuXue Tang Sensitizes Colorectal Cancer Cells to Chemoradiotherapy in vitro and in vivo Model 當歸補血湯於大直腸癌細胞及動物模式中對放射線及化學治療之增敏效果 Shun Ting Chen 陳舜鼎 博士 長庚大學 臨床醫學研究所中醫組 105 Chemotherapy is an important treatment modality for colon cancer, and concurrent chemoradiation therapy (CCRT) is the preferred treatment route for patients with stage II and III rectal cancer. The induction of autophagic cell death is an important process in the development of anticancer therapeutics. We examined how could DangGui BuXue Tang (DBT), a traditional Chinese herbal extract, against colorectal cancer (CRC) and its autophagy-related mechanism in sensitizing colorectal cancer cells for anticancer treatments. The polysaccharide-depleted fraction of DBT (DBT-PD) contains greater amounts of astragaloside IV and ferulic acid than the original formula does. Treatment of the murine colon carcinoma cell line (CT26) with DBT-PD inhibited cell growth, whereas treatment with comparable amounts of purified astragaloside IV and ferulic acid showed no significant effect. Concurrent treatment with DBT-PD increases the growth inhibitory effect of 5-fluorouracil up to 4.39-fold. DBT-PD enhances the effect of radiation therapy (RT) with a sensitizer enhancement ratio (SER) of up to 1.3 fold. It also increases the therapeutic effect of CCRT on CT26 cells. Cells treated with DBP-PD showed ultrastructural changes characteristic of autophagy, including multiple cytoplasmic vacuoles with double-layered membranes, vacuoles containing remnants of degraded organelles, marked swelling and vacuolization of mitochondria, and autolysosome-like vacuoles. In the tumor specimen, the expression of microtubule-associated proteins 1A/1B light chain 3B (LC3B) was upregulated by 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. We conclude that DBT-PD induces autophagy-associated cell death in CT26 cells through the upregulation of Atg7 and modulation of the mTOR/p70s6k signaling pathway, and may have the potential as the chemotherapy or radiotherapy sensitizer in colorectal cancer treatment. T. Y. Lee H. H. Chang Y. J. Chen 李宗諺 張恒鴻 陳裕仁 2017 學位論文 ; thesis 108 zh-TW |
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博士 === 長庚大學 === 臨床醫學研究所中醫組 === 105 === Chemotherapy is an important treatment modality for colon cancer, and concurrent chemoradiation therapy (CCRT) is the preferred treatment route for patients with stage II and III rectal cancer. The induction of autophagic cell death is an important process in the development of anticancer therapeutics. We examined how could DangGui BuXue Tang (DBT), a traditional Chinese herbal extract, against colorectal cancer (CRC) and its autophagy-related mechanism in sensitizing colorectal cancer cells for anticancer treatments.
The polysaccharide-depleted fraction of DBT (DBT-PD) contains greater amounts of astragaloside IV and ferulic acid than the original formula does. Treatment of the murine colon carcinoma cell line (CT26) with DBT-PD inhibited cell growth, whereas treatment with comparable amounts of purified astragaloside IV and ferulic acid showed no significant effect. Concurrent treatment with DBT-PD increases the growth inhibitory effect of 5-fluorouracil up to 4.39-fold. DBT-PD enhances the effect of radiation therapy (RT) with a sensitizer enhancement ratio (SER) of up to 1.3 fold. It also increases the therapeutic effect of CCRT on CT26 cells. Cells treated with DBP-PD showed ultrastructural changes characteristic of autophagy, including multiple cytoplasmic vacuoles with double-layered membranes, vacuoles containing remnants of degraded organelles, marked swelling and vacuolization of mitochondria, and autolysosome-like vacuoles. In the tumor specimen, the expression of microtubule-associated proteins 1A/1B light chain 3B (LC3B) was upregulated by 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.
We conclude that DBT-PD induces autophagy-associated cell death in CT26 cells through the upregulation of Atg7 and modulation of the mTOR/p70s6k signaling pathway, and may have the potential as the chemotherapy or radiotherapy sensitizer in colorectal cancer treatment.
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author2 |
T. Y. Lee |
author_facet |
T. Y. Lee Shun Ting Chen 陳舜鼎 |
author |
Shun Ting Chen 陳舜鼎 |
spellingShingle |
Shun Ting Chen 陳舜鼎 DangGui BuXue Tang Sensitizes Colorectal Cancer Cells to Chemoradiotherapy in vitro and in vivo Model |
author_sort |
Shun Ting Chen |
title |
DangGui BuXue Tang Sensitizes Colorectal Cancer Cells to Chemoradiotherapy in vitro and in vivo Model |
title_short |
DangGui BuXue Tang Sensitizes Colorectal Cancer Cells to Chemoradiotherapy in vitro and in vivo Model |
title_full |
DangGui BuXue Tang Sensitizes Colorectal Cancer Cells to Chemoradiotherapy in vitro and in vivo Model |
title_fullStr |
DangGui BuXue Tang Sensitizes Colorectal Cancer Cells to Chemoradiotherapy in vitro and in vivo Model |
title_full_unstemmed |
DangGui BuXue Tang Sensitizes Colorectal Cancer Cells to Chemoradiotherapy in vitro and in vivo Model |
title_sort |
danggui buxue tang sensitizes colorectal cancer cells to chemoradiotherapy in vitro and in vivo model |
publishDate |
2017 |
url |
http://ndltd.ncl.edu.tw/handle/2469ah |
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