Yan K.-H.Yao C.-J.Chang H.-Y.Lai G.-M.ANN-LII CHENGChuang S.-E.2021-09-012021-09-012010https://www.scopus.com/inward/record.uri?eid=2-s2.0-77949878222&doi=10.1002%2fmc.20593&partnerID=40&md5=3095e75d9e74dd7e63d735d710b76392https://scholars.lib.ntu.edu.tw/handle/123456789/580303Troglitazone (TGZ) is a synthetic thiazolidinedione drug belonging to a group of potent peroxisome proliferator-activated receptor γ (PPARγ) agonists known to inhibit proliferation, alter cell cycle regulation, and induce apoptosis in various cancer cell types. TGZ is an oral anti-type II diabetes drug that can reverse insulin resistance. For more then 100 yr, aspirin, a nonselective cyclooxygenase (COX) inhibitor, has been successfully used as an anti-inflammatory drug. Recently, Aspirin (ASA) and some other nonsteroidal anti-inflammatory drugs (NSAIDs) have drawn much attention for their protective effects against colon cancer and cardiovascular disease; it has been observed that ASA's anti-tumor effect can be attributed to inhibition of cell cycle progression, induction of apoptosis, and inhibition of angiogenesis. In this report we demonstrate for the first time that, when administered in combination, TGZ and ASA can produce a strong synergistic effect in growth inhibition and G1 arrest in lung cancer CL1-0 and A549 cells. Examination by colony formation assay revealed an even more profound synergy. In Western blot, combined TGZ and ASA also could downregulate Cdk2, E2F-1, cyclin B1, cyclin D3 protein, and the ratio of phospho-Rb/Rb. Importantly, apoptosis was synergistically induced by the combination treatment, as evidenced by caspase-3 activation and PARP cleavage. The involvement of PI3K/Akt inhibition and p27 upregulation, as well as hypophosphorylation of Rac1 at ser71, were demonstrated. Taken together, these results suggest that clinically achievable concentrations of TGZ and ASA used in combination may produce a strong anticancer synergy that warrants further investigation for its clinical applications. ? 2009 Wiley-Liss, Inc.Aspirin; NSAID; Pparγ; Synergy; Troglitazone[SDGs]SDG3acetylsalicylic acid; caspase 3; cyclin B1; cyclin D3; cyclin dependent kinase 2; protein kinase B; protein p27; Rac1 protein; transcription factor E2F1; troglitazone; 2,4 thiazolidinedione derivative; acetylsalicylic acid; antineoplastic agent; chroman derivative; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; nonsteroid antiinflammatory agent; peroxisome proliferator activated receptor gamma; troglitazone; antineoplastic activity; apoptosis; article; cancer cell; cancer inhibition; cell cycle arrest; cell cycle G1 phase; controlled study; drug potentiation; enzyme activation; human; human cell; lung cancer; priority journal; protein phosphorylation; cell cycle; cell proliferation; clonogenic assay; drug combination; drug effect; drug potentiation; flow cytometry; lung tumor; metabolism; pathology; tumor cell culture; Western blotting; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; Aspirin; Blotting, Western; Cell Cycle; Cell Proliferation; Chromans; Colony-Forming Units Assay; Drug Synergism; Drug Therapy, Combination; Flow Cytometry; Humans; Lung Neoplasms; Poly(ADP-ribose) Polymerases; PPAR gamma; Thiazolidinediones; Tumor Cells, Culturedjournal article10.1002/mc.20593199082412-s2.0-77949878222