Aqueous extract of Radix Paeoniae Alba and Gallic acid induce G2/M phase arrest and apoptosis in bladder carcinoma
博士 === 中山醫學大學 === 生化暨生物科技研究所 === 98 === The World Health Report attributes an estimated 125,000 death in males and 54,000 deaths in females worldwide as a result of urothelial carcinoma. While many anticancer agents have been used, the side effects and resistance are serious problems. Traditional he...
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ndltd-TW-098CSMU51070182015-10-28T04:07:07Z http://ndltd.ncl.edu.tw/handle/49472642769580481509 Aqueous extract of Radix Paeoniae Alba and Gallic acid induce G2/M phase arrest and apoptosis in bladder carcinoma 白芍及没食子酸經由細胞週期停滯及細胞凋亡抑制膀胱癌生長 Ting-Tsz 歐靜慈 博士 中山醫學大學 生化暨生物科技研究所 98 The World Health Report attributes an estimated 125,000 death in males and 54,000 deaths in females worldwide as a result of urothelial carcinoma. While many anticancer agents have been used, the side effects and resistance are serious problems. Traditional herbal medicines have been used since ancient times to treat malignancies. There has been increasing interest in the biological activity of traditional medicines, and numerous studies report their clinical benefit for cancer. Radix Paeoniae Alba (RPA), is a traditional Chinese medicines, has been shown to treat malignancies. We assayed the components of RPA via determination of HPLC. The components belong to phenolic compounds- gallic acid (GA). We report that RPA and GA significantly inhibit growth of human bladder transitional carcinoma cells (TSGH-8301) and bladder cancer induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (OH-BBN). We observed that RPA and GA treatment of cell resulted induction of apoptosis and arrest in G2/M phase. This induction of apoptosis seems to be mediated via activation of caspase because N-benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluromethylketone significantly reduced apoptosis induced by RPA and GA. Treatment of TSGH-8301 cells with RPA and GA resulted in G2-M phase cell cycle arrest that was associated with a marked decline in protein levels of G2-M regulatory proteins including cyclin-dependent kinase 1 (cdc2), cyclin B1, cell division cycle 25B (Cdc25B) and Cdc25C. We also reported that RPA- and GA-mediated growth inhibition of TSGH-8301 cells was correlated with activation of Cip1/p21 and checkpoint kinase 2 (Chk2). Additional mechanistic studies showed that GA induces phosphorylation of Cdc25C at Ser-216. This mechanism leads to its translocation from nucleus to cytoplasm resulting in an increase binding with 14-3-3β. When treated with GA, phosphorylated Cdc25C can be activated by ataxia telangiectasia mutated (ATM)-checkpoint kinase 2 (Chk2). It might be a DNA damage response proved by Ser-139 phosphorylation of histine H2A.X. Herein, we further evaluated urinary bladder cancer by RPA and GA in a model of bladder cancer induced by OH-BBN. RPA and GA strongly arrest OH-BBN-induced tumor progression at the stage of mucosal dysplasia with a striking reduction in papillary nodular dysplasia. Analysis of tumors from RPA-treated rats showed significant decrease in the expression of Bcl2, cyclin D1, and PCNA, and increase in the expression of p-Chk2 (Thr-68), Bax, and Cip1/p21. Our data suggest that RPA could be developed as an agent against bladder cancer. Key words: Radix Paeoniae Alba, gallic acid, cell cycle, apoptosis, OH-BBN, Chk2, ATM. 王朝鐘 李彗禎 2010 學位論文 ; thesis 141 zh-TW |
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博士 === 中山醫學大學 === 生化暨生物科技研究所 === 98 === The World Health Report attributes an estimated 125,000 death in males and 54,000 deaths in females worldwide as a result of urothelial carcinoma. While many anticancer agents have been used, the side effects and resistance are serious problems. Traditional herbal medicines have been used since ancient times to treat malignancies. There has been increasing interest in the biological activity of traditional medicines, and numerous studies report their clinical benefit for cancer. Radix Paeoniae Alba (RPA), is a traditional Chinese medicines, has been shown to treat malignancies. We assayed the components of RPA via determination of HPLC. The components belong to phenolic compounds- gallic acid (GA). We report that RPA and GA significantly inhibit growth of human bladder transitional carcinoma cells (TSGH-8301) and bladder cancer induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (OH-BBN). We observed that RPA and GA treatment of cell resulted induction of apoptosis and arrest in G2/M phase. This induction of apoptosis seems to be mediated via activation of caspase because N-benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluromethylketone significantly reduced apoptosis induced by RPA and GA. Treatment of TSGH-8301 cells with RPA and GA resulted in G2-M phase cell cycle arrest that was associated with a marked decline in protein levels of G2-M regulatory proteins including cyclin-dependent kinase 1 (cdc2), cyclin B1, cell division cycle 25B (Cdc25B) and Cdc25C. We also reported that RPA- and GA-mediated growth inhibition of TSGH-8301 cells was correlated with activation of Cip1/p21 and checkpoint kinase 2 (Chk2). Additional mechanistic studies showed that GA induces phosphorylation of Cdc25C at Ser-216. This mechanism leads to its translocation from nucleus to cytoplasm resulting in an increase binding with 14-3-3β. When treated with GA, phosphorylated Cdc25C can be activated by ataxia telangiectasia mutated (ATM)-checkpoint kinase 2 (Chk2). It might be a DNA damage response proved by Ser-139 phosphorylation of histine H2A.X. Herein, we further evaluated urinary bladder cancer by RPA and GA in a model of bladder cancer induced by OH-BBN. RPA and GA strongly arrest OH-BBN-induced tumor progression at the stage of mucosal dysplasia with a striking reduction in papillary nodular dysplasia. Analysis of tumors from RPA-treated rats showed significant decrease in the expression of Bcl2, cyclin D1, and PCNA, and increase in the expression of p-Chk2 (Thr-68), Bax, and Cip1/p21. Our data suggest that RPA could be developed as an agent against bladder cancer.
Key words: Radix Paeoniae Alba, gallic acid, cell cycle, apoptosis, OH-BBN, Chk2, ATM.
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author2 |
王朝鐘 |
author_facet |
王朝鐘 Ting-Tsz 歐靜慈 |
author |
Ting-Tsz 歐靜慈 |
spellingShingle |
Ting-Tsz 歐靜慈 Aqueous extract of Radix Paeoniae Alba and Gallic acid induce G2/M phase arrest and apoptosis in bladder carcinoma |
author_sort |
Ting-Tsz |
title |
Aqueous extract of Radix Paeoniae Alba and Gallic acid induce G2/M phase arrest and apoptosis in bladder carcinoma |
title_short |
Aqueous extract of Radix Paeoniae Alba and Gallic acid induce G2/M phase arrest and apoptosis in bladder carcinoma |
title_full |
Aqueous extract of Radix Paeoniae Alba and Gallic acid induce G2/M phase arrest and apoptosis in bladder carcinoma |
title_fullStr |
Aqueous extract of Radix Paeoniae Alba and Gallic acid induce G2/M phase arrest and apoptosis in bladder carcinoma |
title_full_unstemmed |
Aqueous extract of Radix Paeoniae Alba and Gallic acid induce G2/M phase arrest and apoptosis in bladder carcinoma |
title_sort |
aqueous extract of radix paeoniae alba and gallic acid induce g2/m phase arrest and apoptosis in bladder carcinoma |
publishDate |
2010 |
url |
http://ndltd.ncl.edu.tw/handle/49472642769580481509 |
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