A novel peroxisome proliferator-activated receptor α/γ agonist, BPR1H0101, inhibits topoisomerase II catalytic activity in human cancer cells

Yu Hsun Kao, Hsing Pang Hsieh, Santhosh Kumar Chitlimalla, Wen Yu Pan, Ching Chuan Kuo, Yuan Chin Tsai, Wen Hsing Lin, Shuang En Chuang, Jang Yang Chang

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6 Citations (Scopus)


Peroxisome proliferator-activated receptor (PPAR) γ agonists are used clinically for treating diabetes mellitus and cancer. 2-Methyl-2[(1-{3-phenyl- 7-propylbenzol[d]isoxazol-6-yl}oxy)propyl]-1H-4-indolyl) oxy]propanoic acid (BPR1H0101) is a novel synthetic indole-based compound, discovered through research to identify new PPARγ agonists, and it acts as a dual agonist for PPARγ and PPARα. Isobologram analysis demonstrated that BPR1H0101 is capable of antagonistic interaction with the topoisomerase (topo) II poison, VP16. A study of its mechanism showed that BPR1H0101 could inhibit the catalytic activity of topo II in vitro, but did not produce detectable topo II-mediated DNA strand breaks in human oral cancer KB cells. Furthermore, BPR1H0101 could inhibit VP16-induced topo II-mediated DNA cleavage and ataxia-telangiectasia- mutated phosphorylation in KB cells. The results suggest that BPR1H0101 can interfere with the topo II reaction by inhibiting catalytic activity before the formation of the intermediate cleavable complex; consequently, it can impede VP16-induced topo II-mediated DNA cleavage and cell death. This is the first identified PPARα/γ agonist that can serve as a topo II catalytic inhibitor, to interfere with VP16-induced cell death. The result might have relevance to the clinical use of the PPARα/γ agonist in combination chemotherapy.

Original languageEnglish
Pages (from-to)151-158
Number of pages8
JournalAnti-Cancer Drugs
Issue number2
Publication statusPublished - Feb 2008
Externally publishedYes



  • Peroxisome proliferator-activated receptor α/γ
  • Topoisomerase II
  • VP16

ASJC Scopus subject areas

  • Pharmacology
  • Cancer Research
  • Oncology

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