Abstract
BackgroundPeroxisome proliferator-activated receptor γ (PPARγ) agonists frequently induce cell death in human non-small-cell lung cancer (NSCLC) cells. However, majority of NSCLC patients acquire resistance after cancer therapy, and it is still unclear.MethodsIn this study we investigated the apoptotic mechanism and the anti-cancer effects of a novel purine-based PPARγ agonist, CB11 (8-(2-aminophenyl)-3-butyl-1,6,7-trimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione), on human NSCLC cells. CB11 mediates PPARγ-dependent cell death, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) collapse, cell cycle arrest, lactate dehydrogenase (LDH) cytotoxicity, and caspase-3 activity in human NSCLC cells.ResultsCB11 causes cell death via ROS-mediated ATM-p53-GADD45α signalling in human NSCLC cells, and diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, decreases cell death by inhibiting CB11-mediated ATM signalling. In a xenograft experiment, CB11 dramatically reduced tumour volume when compared to a control group. Furthermore, CB11 induced cell death by inhibiting epithelial-to-mesenchymal transition (EMT) under radiation exposure in radiation-resistant human NSCLC cells. However, PPARγ deficiency inhibited cell death by blocking the ATM-p53 axis in radiation/CB11-induced radiation-resistant human NSCLC cells.ConclusionsTaken together, our results suggest that CB11, a novel PPARγ agonist, may be a novel anti-cancer agent, and it could be useful in a therapeutic strategy to overcome radio-resistance in radiation-exposed NSCLC.
Highlights
Peroxisome proliferator-activated receptor γ (PPARγ) agonists frequently induce cell death in human non-small-cell lung cancer (NSCLC) cells
We evaluated the effects of a novel PPARγ agonist candidate, CB11, on apoptosis and investigated the mechanisms underlying these effects in NSCLC cells exposed and not exposed to radiation
PPARγ is widely expressed in various tumours, and synthetic PPARγ ligands have been shown to cause growth inhibition and apoptosis in NSCLC cells.[40]
Summary
Peroxisome proliferator-activated receptor γ (PPARγ) agonists frequently induce cell death in human non-small-cell lung cancer (NSCLC) cells. PPARγ deficiency inhibited cell death by blocking the ATM-p53 axis in radiation/CB11-induced radiation-resistant human NSCLC cells. CONCLUSIONS: Taken together, our results suggest that CB11, a novel PPARγ agonist, may be a novel anti-cancer agent, and it could be useful in a therapeutic strategy to overcome radio-resistance in radiation-exposed NSCLC. PPARγ ligands inhibit growth and induce apoptosis in lung cancer cells via alternative mechanisms, which are dependent on the growth conditions and ligands utilised.[18]
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