BPR1K653, a novel aurora kinase inhibitor, exhibits potent anti-proliferative activity in MDR1 (P-gp170)-mediated multidrug-resistant cancer cells

Chun Hei Antonio Cheung, Wen Hsing Lin, John Tsu An HsuJohn, Tzyh Chyuan Hour, Teng Kuang Yeh, Shengkai Ko, Tzu Wen Lien, Mohane Selvaraj Coumar, Jin Fen Liu, Wen Yang Lai, Hui Yi Shiao, Tian Ren Lee, Hsing Pang Hsieh, Jang Yang Chang

研究成果: Article

13 引文 斯高帕斯(Scopus)

摘要

Background: Over-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells. Principal Findings: BPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats. Conclusions and Significance: BPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments.

原文English
文章編號e23485
期刊PloS one
6
發行號8
DOIs
出版狀態Published - 2011 八月 24

    指紋

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

引用此

Cheung, C. H. A., Lin, W. H., HsuJohn, J. T. A., Hour, T. C., Yeh, T. K., Ko, S., Lien, T. W., Coumar, M. S., Liu, J. F., Lai, W. Y., Shiao, H. Y., Lee, T. R., Hsieh, H. P., & Chang, J. Y. (2011). BPR1K653, a novel aurora kinase inhibitor, exhibits potent anti-proliferative activity in MDR1 (P-gp170)-mediated multidrug-resistant cancer cells. PloS one, 6(8), [e23485]. https://doi.org/10.1371/journal.pone.0023485