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

Abstract	Peroxisome proliferator-activated receptor (PPAR) gamma 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 PPARgamma agonists, and it acts as a dual agonist for PPARgamma and PPARalpha. 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 PPARalpha/gamma 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 PPARalpha/gamma agonist in combination chemotherapy.
Authors	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
Journal	Anti-cancer drugs (Anticancer Drugs) Vol. 19 Issue 2 Pg. 151-8 (Feb 2008) ISSN: 0959-4973 [Print] England
PMID	18176111 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	2-methyl-2-((1-(3-phenyl-7-propylbenzo(d)isoxazol-6-yl)oxy)propyl)-1H-4-indolyloxypropanoic acid Antineoplastic Agents, Phytogenic Cell Cycle Proteins Chromans DNA, Circular DNA-Binding Proteins Indoles Peroxisome Proliferator-Activated Receptors Propionates RNA, Small Interfering Thiazolidinediones Topoisomerase II Inhibitors Tumor Suppressor Proteins Etoposide ATM protein, human Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases DNA Topoisomerases, Type II Troglitazone
Topics	Antineoplastic Agents, Phytogenic (pharmacology) Ataxia Telangiectasia Mutated Proteins Blotting, Western Catalysis (drug effects) Cell Cycle Proteins (metabolism) Chromans (pharmacology) DNA Breaks (drug effects) DNA Cleavage (drug effects) DNA Topoisomerases, Type II (metabolism) DNA, Circular (drug effects) DNA-Binding Proteins (metabolism) Dose-Response Relationship, Drug Drug Antagonism Etoposide (pharmacology) Humans Indoles (chemistry, pharmacology) KB Cells Molecular Structure Peroxisome Proliferator-Activated Receptors (agonists, genetics, metabolism) Phosphorylation (drug effects) Propionates (chemistry, pharmacology) Protein Serine-Threonine Kinases (metabolism) RNA, Small Interfering (genetics) Thiazolidinediones (pharmacology) Topoisomerase II Inhibitors Transcriptional Activation (drug effects) Transfection Troglitazone Tumor Suppressor Proteins (metabolism)

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