title: Dual inhibition of topoisomerase I and tubulin polymerization by BPR0Y007, a novel cytotoxic agent.
abstract: 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 G(2)/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 IC(50) of BPR0Y007 for various human cancer cell lines ranged from 1 to 8 microM. 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.
authors.affiliation: Division of Cancer Research, National Health Research Institutes, 7, Chung-Shan South Road, Taipei, Taiwan, ROC. jychang@nhri.org.tw
authors.forename: Jang-Yang
authors.initials: JY
authors.lastname: Chang
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Hsieh
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Pan
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Liou
authors.forename: Shian-Jy
authors.initials: SJ
authors.lastname: Bey
authors.forename: Li-Tzong
authors.initials: LT
authors.lastname: Chen
authors.forename: Jin-Fen
authors.initials: JF
authors.lastname: Liu
authors.forename: Jen-Shin
authors.initials: JS
authors.lastname: Song
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002166:Camptothecin / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D007624:KB Cells; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D059004:Topoisomerase I Inhibitors; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D059004:Topoisomerase I Inhibitors; D014404:Tubulin; D005047:Etoposide; D002166:Camptothecin