5k, a novel β-O-demethyl-epipodophyllotoxin analogue, inhibits the proliferation of cancer cells in vitro and in vivo via the induction of G2 arrest and apoptosis
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- 作者：Danqing Xu (1)
Ji Cao (1)
Shijing Qian (1)
Lin Li (1)
Chunqi Hu (2)
Qinjie Weng (1)
Jianshu Lou (1)
Difeng Zhu (1)
Hong Zhu (1)
Yongzhou Hu (2)
Qiaojun He (1) qiaojunhe@zju.edu.cn
Bo Yang (1) yang924@zju.edu.cn - 关键词：Topo II inhibitor – MDR – DNA damage – G2 arrest – Apoptosis
- 刊名：Investigational New Drugs
- 出版年：2011
- 出版时间：October 2011
- 年：2011
- 卷：29
- 期：5
- 页码：786-799
- 全文大小：927.2 KB
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- 刊物类别：Medicine
- 刊物主题：Medicine & Public Health
Oncology
Pharmacology and Toxicology - 出版者：Springer Netherlands
- ISSN：1573-0646
文摘
Etoposide (VP-16), a topoisomerase II (Topo II) inhibitor, has been widely used to treat malignancies. Its clinical application, however, has been hindered by the rise of acquired multidrug resistance (MDR). Here, we report that 4β-{[4-(pyrrolidin-1-ylmethyl)phenyl]amino}-4′-O-Demethyl-4-Epipodophyllotoxin (5k), a novel β-O-demethyl-epipodophyllotoxin analogue, possesses higher antitumor activity than its parent compound (VP-16) in a panel of various human tumor cell lines. More importantly, it was also effective against MDR cells both in vitro and in vivo. Using a KB/VCR MDR tumor xenograft model that overexpresses P-gp, 5k (2.5 mg/kg) exhibited a 2.4-fold higher growth inhibition rate versus VP-16 (5 mg/kg). In contrast, 5k and VP-16 displayed similar antitumor activities in a KB tumor xenograft model. Molecular and cellular mechanism studies revealed that 5k targeted Topo II by trapping DNA-Topo II cleavage complexes that could directly cause DNA damage. There were two distinct cellular responses to DNA damage elicited by the treatment with 5k: at low concentrations (20–80 nM), mitotic entry was arrested through the suppression of the activity of Cyclin B1/Cdc 2 complexes via the ATM/ATR signaling pathway; at high concentrations (1.25–5.00 μM), 5k-induced apoptotic signaling was mediated by the mitochondrial death pathways. Collectively, these data demonstrate the potential value of 5k as an antitumor drug candidate that should be further developed.