title: GL3, a Novel 4β-Anilino-4'-O-Demethyl-4-Desoxypodophyllotoxin Analog, Traps Topoisomerase II Cleavage Complexes and Exerts Anticancer Activities.
abstract: 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 (IC(50)) 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.
authors: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China.
authors: Xiao-Chun
authors: XC
authors: Yang
authors: Shi-Jing
authors: SJ
authors: Qian
authors: Li
authors: L
authors: Wang
authors: Si-Da
authors: SD
authors: Liao
authors: Ji
authors: J
authors: Cao
authors: Yong-Zhou
authors: YZ
authors: Hu
authors: Qiao-Jun
authors: QJ
authors: He
authors: Hong
authors: H
authors: Zhu
authors: Bo
authors: B
authors: Yang