GL3, a Novel 4β-Anilino-4′-O-Demethyl-4-Desoxypodophyllotoxin Analog, Traps Topoisomerase II Cleavage Complexes and Exerts Anticancer Activities
| Autor: | Si-Da Liao, Yongzhou Hu, Li Wang, Ji Cao, Xiaochun Yang, Shijing Qian, Hong Zhu, Qiaojun He, Bo Yang |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
chemistry.chemical_classification
Cancer Research Cell cycle checkpoint biology Stereochemistry Topoisomerase lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Cleavage (embryo) lcsh:RC254-282 Toxicology Enzyme Oncology chemistry Cell culture Apoptosis biology.protein medicine Cytotoxicity Aclarubicin medicine.drug |
| Zdroj: | Translational Oncology, Vol 6, Iss 1, Pp 75-82 (2013) |
| ISSN: | 1936-5233 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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