Sophoridinol derivative 05D induces tumor cells apoptosis by topoisomerase1-mediated DNA breakage
Wuli Zhao, Caixia Zhang, Chongwen Bi, Cheng Ye, Danqing Song, Xiujun Liu, Rongguang Shao Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, Peop...
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doaj-36a7d1e45a524903a3d70abf5c2b36ec2020-11-24T21:15:26ZengDove Medical PressOncoTargets and Therapy1178-69302016-05-012016Issue 12805281726881Sophoridinol derivative 05D induces tumor cells apoptosis by topoisomerase1-mediated DNA breakageZhao WZhang CBi CYe CSong DLiu XShao RWuli Zhao, Caixia Zhang, Chongwen Bi, Cheng Ye, Danqing Song, Xiujun Liu, Rongguang Shao Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of China Abstract: Sophoridine is a quinolizidine natural product of Sophora alopecuroides and has been applied for treatment of malignant trophoblastic tumors. Although characterized by low toxicity, the limited-spectrum antitumor activity hinders its further applications. 05D, a derivative of sophoridine, exhibits a better anticancer activity on diverse cancer cells, including solid tumors, and hematologic malignancy. It could inhibit topoisomerase 1 (top1) activity by stabilizing DNA–top1 complex and induce mitochondria-mediated apoptosis by promoting DNA single- and double-strand breakage mediated by top1. Also, 05D induced HCT116 cells arrest at G1 phase by inactivating CDK2/CDK4–Rb–E2F and cyclinD1–CDK4–p21 checkpoint signal pathways. 05D suppressed the ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) activation and decreased 53BP level, which contributed to DNA damage repair, suggesting that the novel compound 05D might be helpful to improve the antitumor activity of DNA damaging agent by repressing ATM and ATR activation and 53BP level. In addition, the priorities in molecular traits and druggability, such as a simple structure and formulation for oral administration, further prove 05D to be a promising targeting topoisomerase agent. Keywords: topoisomerase inhibitor, topoisomerase 1, DNA breakage, sophoridinol, anticancer, apoptosis, cell cyclehttps://www.dovepress.com/sophoridinol-derivative-05d-induces-tumor-cells-apoptosis-by-topoisome-peer-reviewed-article-OTTtopoisomerase inhibitortopoisomerase1DNA breakagesophoridinolanticancerapoptosiscell cycle |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zhao W Zhang C Bi C Ye C Song D Liu X Shao R |
spellingShingle |
Zhao W Zhang C Bi C Ye C Song D Liu X Shao R Sophoridinol derivative 05D induces tumor cells apoptosis by topoisomerase1-mediated DNA breakage OncoTargets and Therapy topoisomerase inhibitor topoisomerase1 DNA breakage sophoridinol anticancer apoptosis cell cycle |
author_facet |
Zhao W Zhang C Bi C Ye C Song D Liu X Shao R |
author_sort |
Zhao W |
title |
Sophoridinol derivative 05D induces tumor cells apoptosis by topoisomerase1-mediated DNA breakage |
title_short |
Sophoridinol derivative 05D induces tumor cells apoptosis by topoisomerase1-mediated DNA breakage |
title_full |
Sophoridinol derivative 05D induces tumor cells apoptosis by topoisomerase1-mediated DNA breakage |
title_fullStr |
Sophoridinol derivative 05D induces tumor cells apoptosis by topoisomerase1-mediated DNA breakage |
title_full_unstemmed |
Sophoridinol derivative 05D induces tumor cells apoptosis by topoisomerase1-mediated DNA breakage |
title_sort |
sophoridinol derivative 05d induces tumor cells apoptosis by topoisomerase1-mediated dna breakage |
publisher |
Dove Medical Press |
series |
OncoTargets and Therapy |
issn |
1178-6930 |
publishDate |
2016-05-01 |
description |
Wuli Zhao, Caixia Zhang, Chongwen Bi, Cheng Ye, Danqing Song, Xiujun Liu, Rongguang Shao Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of China Abstract: Sophoridine is a quinolizidine natural product of Sophora alopecuroides and has been applied for treatment of malignant trophoblastic tumors. Although characterized by low toxicity, the limited-spectrum antitumor activity hinders its further applications. 05D, a derivative of sophoridine, exhibits a better anticancer activity on diverse cancer cells, including solid tumors, and hematologic malignancy. It could inhibit topoisomerase 1 (top1) activity by stabilizing DNA–top1 complex and induce mitochondria-mediated apoptosis by promoting DNA single- and double-strand breakage mediated by top1. Also, 05D induced HCT116 cells arrest at G1 phase by inactivating CDK2/CDK4–Rb–E2F and cyclinD1–CDK4–p21 checkpoint signal pathways. 05D suppressed the ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) activation and decreased 53BP level, which contributed to DNA damage repair, suggesting that the novel compound 05D might be helpful to improve the antitumor activity of DNA damaging agent by repressing ATM and ATR activation and 53BP level. In addition, the priorities in molecular traits and druggability, such as a simple structure and formulation for oral administration, further prove 05D to be a promising targeting topoisomerase agent. Keywords: topoisomerase inhibitor, topoisomerase 1, DNA breakage, sophoridinol, anticancer, apoptosis, cell cycle |
topic |
topoisomerase inhibitor topoisomerase1 DNA breakage sophoridinol anticancer apoptosis cell cycle |
url |
https://www.dovepress.com/sophoridinol-derivative-05d-induces-tumor-cells-apoptosis-by-topoisome-peer-reviewed-article-OTT |
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