Dual inhibition of topoisomerase I and tubulin polymerization by BPR0Y007, a novel cytotoxic agent

Jang Yang Chang, Hsing Pang Hsieh, Wen Yu Pan, Jing Ping Liou, Shian Jy Bey, Li Tzong Chen, Jin Fen Liu, Jen Shin Song

研究成果: 雜誌貢獻文章

21 引文 斯高帕斯(Scopus)

摘要

Through the screening of DNA topoisomerase I (Top I) inhibitors, a new cytotoxic agent, BPR0Y007 [2,5-bis(4-hydroxy-3-methoxybenzylidene)cyclopentanone], was identified. BPR0Y007 was less potent than camptothecin (CPT) in the inhibition of Top I in vitro. Also, in vitro data showed that BPR0Y007 induces DNA cleavage in the presence of Top I at micromolar concentrations, with a cleavage specificity similar to that of CPT. High concentrations of BPR0Y007 did not produce detectable DNA unwinding, suggesting that BPR0Y007 is not a DNA intercalator. However, BPR0Y007 displaced Hoechst 33342 dye, suggesting that BPR0Y007 binds to DNA at the Hoechst 33342 binding site. Furthermore, BPR0Y007 generated protein-linked DNA breaks in a cell-based study. Cell cycle analysis demonstrated that the cell cycle effect of BPR0Y007 differs from that of CPT. Cells accumulated in the S-phase when treated with high concentrations of CPT, whereas cells accumulated gradually in the G2/M phase when treated with increasing concentrations of BPR0Y007. Further studies showed that BPR0Y007 inhibits tubulin polymerization in vivo and in vitro, and induces apoptosis in a concentration-dependent manner. No cross-resistance with BPR0Y007 was observed in CPT-, VP-16-, or vincristine-resistant cell lines. The IC50 of BPR0Y007 for various human cancer cell lines ranged from 1 to 8μM. Taken together, these results suggest that BPR0Y007 acts on both Top I and tubulin. Given its unique biochemical mechanisms of action, BPR0Y007 warrants exploration as an antitumor compound.

原文英語
頁(從 - 到)2009-2019
頁數11
期刊Biochemical Pharmacology
65
發行號12
DOIs
出版狀態已發佈 - 六月 15 2003
對外發佈Yes

    指紋

ASJC Scopus subject areas

  • Pharmacology

引用此

Chang, J. Y., Hsieh, H. P., Pan, W. Y., Liou, J. P., Bey, S. J., Chen, L. T., Liu, J. F., & Song, J. S. (2003). Dual inhibition of topoisomerase I and tubulin polymerization by BPR0Y007, a novel cytotoxic agent. Biochemical Pharmacology, 65(12), 2009-2019. https://doi.org/10.1016/S0006-2952(03)00197-7