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

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2009-2019
Number of pages11
JournalBiochemical Pharmacology
Issue number12
Publication statusPublished - Jun 15 2003
Externally publishedYes


  • Dual inhibitor
  • Topoisomerase I
  • Tubulin

ASJC Scopus subject areas

  • Pharmacology


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