A novel peroxisome proliferator-activated receptor alpha/gamma agonist, BPR1H0101, inhibits topoisomerase II catalytic activity in human cancer cells.
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.
Kao
Yu-Hsun
YH
Graduate Institute of Life Sciences, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Hsieh
Hsing-Pang
HP
Chitlimalla
Santhosh Kumar
SK
Pan
Wen-Yu
WY
Kuo
Ching-Chuan
CC
Tsai
Yuan-Chin
YC
Lin
Wen-Hsing
WH
Chuang
Shuang-En
SE
Chang
Jang-Yang
JY
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D002384:Catalysis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D053960:DNA Breaks / Q000187:drug effects; D053837:DNA Cleavage / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004270:DNA, Circular / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D007624:KB Cells; D015394:Molecular Structure; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011422:Propionates / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D000077288:Troglitazone; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C527792:2-methyl-2-((1-(3-phenyl-7-propylbenzo(d)isoxazol-6-yl)oxy)propyl)-1H-4-indolyloxypropanoic acid; D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D002839:Chromans; D004270:DNA, Circular; D004268:DNA-Binding Proteins; D007211:Indoles; D047492:Peroxisome Proliferator-Activated Receptors; D011422:Propionates; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; D059005:Topoisomerase II Inhibitors; D025521:Tumor Suppressor Proteins; D005047:Etoposide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D004250:DNA Topoisomerases, Type II; D000077288:Troglitazone