GL3, a Novel 4β-Anilino-4′-O-Demethyl-4-Desoxypodophyllotoxin Analog, Traps Topoisomerase II Cleavage Complexes and Exerts Anticancer Activities
A novel VP-16 derivative, 4β-[N -(4‴-acetyloxyl-phenyl-1‴-carbonyl)-4″-aminoanilino]-4′-O-demethyl-4-desoxypodophyllotoxin (GL3), displayed a wide range of cytotoxicity in a panel of human tumor cell lines, with half-maximal inhibitory concentration (IC50) values ranging from 0.82 to 4.88 µM, much l...
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doaj-a8e7dbe1fef94dbc9bdb59c0dda0d1582020-11-25T01:38:40ZengElsevierTranslational Oncology1936-52332013-02-01617582GL3, a Novel 4β-Anilino-4′-O-Demethyl-4-Desoxypodophyllotoxin Analog, Traps Topoisomerase II Cleavage Complexes and Exerts Anticancer ActivitiesXiao-Chun Yang0Shi-Jing Qian1Li Wang2Si-Da Liao3Ji Cao4Yong-Zhou Hu5Qiao-Jun He6Hong Zhu7Bo Yang8Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of ChinaInstitute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of ChinaZhejiang University-Ecole Normole Superienre Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of ChinaInstitute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of ChinaInstitute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of ChinaZhejiang University-Ecole Normole Superienre Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of ChinaInstitute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of ChinaInstitute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China; Address all correspondence to: Dr Hong Zhu or Dr Bo Yang, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of ChinaInstitute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of ChinaA novel VP-16 derivative, 4β-[N -(4‴-acetyloxyl-phenyl-1‴-carbonyl)-4″-aminoanilino]-4′-O-demethyl-4-desoxypodophyllotoxin (GL3), displayed a wide range of cytotoxicity in a panel of human tumor cell lines, with half-maximal inhibitory concentration (IC50) values ranging from 0.82 to 4.88 µM, much less than that of VP-16 (4.18–39.43 µM). Importantly, GL3 induces more significant apoptosis and cell cycle arrest than VP-16. The molecular and cellular machinery studies showed that GL3 functions as a topoisomerase II (Top 2) poison through direct binding to the enzyme, and the advanced cell-killing activities of GL3 were ascribed to its potent effects on trapping Top 2-DNA cleavage complex, Moreover, GL3-triggered DNA double-strand breaks and apoptotic cell death were in a Top 2-dependent manner, because the catalytic inhibitor aclarubicin attenuated these biologic consequences caused by Top 2 poisoning in GL3-treated cells. Taken together, among a series of 4β-anilino-4′-O-demethyl-4-desoxypodophyllotoxin analog, GL3 stood out by its improved anticancer activity and well-defined Top 2 poisoning mechanisms, which merited the potential value of GL3 as an anticancer lead compound/drug candidate deserving further development.http://www.sciencedirect.com/science/article/pii/S1936523313800447 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xiao-Chun Yang Shi-Jing Qian Li Wang Si-Da Liao Ji Cao Yong-Zhou Hu Qiao-Jun He Hong Zhu Bo Yang |
spellingShingle |
Xiao-Chun Yang Shi-Jing Qian Li Wang Si-Da Liao Ji Cao Yong-Zhou Hu Qiao-Jun He Hong Zhu Bo Yang GL3, a Novel 4β-Anilino-4′-O-Demethyl-4-Desoxypodophyllotoxin Analog, Traps Topoisomerase II Cleavage Complexes and Exerts Anticancer Activities Translational Oncology |
author_facet |
Xiao-Chun Yang Shi-Jing Qian Li Wang Si-Da Liao Ji Cao Yong-Zhou Hu Qiao-Jun He Hong Zhu Bo Yang |
author_sort |
Xiao-Chun Yang |
title |
GL3, a Novel 4β-Anilino-4′-O-Demethyl-4-Desoxypodophyllotoxin Analog, Traps Topoisomerase II Cleavage Complexes and Exerts Anticancer Activities |
title_short |
GL3, a Novel 4β-Anilino-4′-O-Demethyl-4-Desoxypodophyllotoxin Analog, Traps Topoisomerase II Cleavage Complexes and Exerts Anticancer Activities |
title_full |
GL3, a Novel 4β-Anilino-4′-O-Demethyl-4-Desoxypodophyllotoxin Analog, Traps Topoisomerase II Cleavage Complexes and Exerts Anticancer Activities |
title_fullStr |
GL3, a Novel 4β-Anilino-4′-O-Demethyl-4-Desoxypodophyllotoxin Analog, Traps Topoisomerase II Cleavage Complexes and Exerts Anticancer Activities |
title_full_unstemmed |
GL3, a Novel 4β-Anilino-4′-O-Demethyl-4-Desoxypodophyllotoxin Analog, Traps Topoisomerase II Cleavage Complexes and Exerts Anticancer Activities |
title_sort |
gl3, a novel 4β-anilino-4′-o-demethyl-4-desoxypodophyllotoxin analog, traps topoisomerase ii cleavage complexes and exerts anticancer activities |
publisher |
Elsevier |
series |
Translational Oncology |
issn |
1936-5233 |
publishDate |
2013-02-01 |
description |
A novel VP-16 derivative, 4β-[N -(4‴-acetyloxyl-phenyl-1‴-carbonyl)-4″-aminoanilino]-4′-O-demethyl-4-desoxypodophyllotoxin (GL3), displayed a wide range of cytotoxicity in a panel of human tumor cell lines, with half-maximal inhibitory concentration (IC50) values ranging from 0.82 to 4.88 µM, much less than that of VP-16 (4.18–39.43 µM). Importantly, GL3 induces more significant apoptosis and cell cycle arrest than VP-16. The molecular and cellular machinery studies showed that GL3 functions as a topoisomerase II (Top 2) poison through direct binding to the enzyme, and the advanced cell-killing activities of GL3 were ascribed to its potent effects on trapping Top 2-DNA cleavage complex, Moreover, GL3-triggered DNA double-strand breaks and apoptotic cell death were in a Top 2-dependent manner, because the catalytic inhibitor aclarubicin attenuated these biologic consequences caused by Top 2 poisoning in GL3-treated cells. Taken together, among a series of 4β-anilino-4′-O-demethyl-4-desoxypodophyllotoxin analog, GL3 stood out by its improved anticancer activity and well-defined Top 2 poisoning mechanisms, which merited the potential value of GL3 as an anticancer lead compound/drug candidate deserving further development. |
url |
http://www.sciencedirect.com/science/article/pii/S1936523313800447 |
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