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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents, Phytogenic / pharmacology
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Ataxia Telangiectasia Mutated Proteins
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Blotting, Western
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Catalysis / drug effects
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Cell Cycle Proteins / metabolism
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Chromans / pharmacology
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DNA Breaks / drug effects
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DNA Cleavage / drug effects
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DNA Topoisomerases, Type II / metabolism
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DNA, Circular / drug effects
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DNA-Binding Proteins / metabolism
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Dose-Response Relationship, Drug
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Drug Antagonism
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Etoposide / pharmacology
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Humans
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Indoles / chemistry
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Indoles / pharmacology*
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KB Cells
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Molecular Structure
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Peroxisome Proliferator-Activated Receptors / agonists*
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Peroxisome Proliferator-Activated Receptors / genetics
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Peroxisome Proliferator-Activated Receptors / metabolism
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Phosphorylation / drug effects
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Propionates / chemistry
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Propionates / pharmacology*
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Protein Serine-Threonine Kinases / metabolism
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RNA, Small Interfering / genetics
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Thiazolidinediones / pharmacology
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Topoisomerase II Inhibitors*
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Transcriptional Activation / drug effects
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Transfection
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Troglitazone
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Tumor Suppressor Proteins / metabolism
Substances
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2-methyl-2-((1-(3-phenyl-7-propylbenzo(d)isoxazol-6-yl)oxy)propyl)-1H-4-indolyloxypropanoic acid
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Antineoplastic Agents, Phytogenic
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Cell Cycle Proteins
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Chromans
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DNA, Circular
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DNA-Binding Proteins
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Indoles
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Peroxisome Proliferator-Activated Receptors
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Propionates
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RNA, Small Interfering
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Thiazolidinediones
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Topoisomerase II Inhibitors
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Tumor Suppressor Proteins
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Etoposide
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases
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DNA Topoisomerases, Type II
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Troglitazone