drf-2725 has been researched along with ciglitazone* in 1 studies
1 other study(ies) available for drf-2725 and ciglitazone
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Structurally diverse peroxisome proliferator-activated receptor agonists induce apoptosis in human uro-epithelial cells by a receptor-independent mechanism involving store-operated calcium channels.
Peroxisome proliferator-activated receptors (PPARs) are implicated in epithelial cell proliferation and differentiation, but investigation has been confounded by potential off-target effects of some synthetic PPAR ligands. Our aim was to determine mechanisms underlying the pro-apoptotic effect of synthetic PPAR agonists in normal human bladder uro-epithelial (urothelial) cells and to reconcile this with the role of PPARs in urothelial cytodifferentiation.. Normal human urothelial (NHU) cells were grown as non-immortal lines in vitro and exposed to structurally diverse agonists ciglitazone, troglitazone, rosiglitazone (PPARgamma), ragaglitazar (PPARalpha/gamma), fenofibrate (PPARalpha) and L165041 (PPARbeta/delta).. NHU cells underwent apoptosis following acute exposure to ciglitazone, troglitazone or ragaglitazar, but not fenofibrate, L165041 or rosiglitazone, and this was independent of ERK or p38 MAP-kinase activation. Pro-apoptotic agonists induced sustained increases in intracellular calcium, whereas removal of extracellular calcium altered the kinetics of ciglitazone-mediated calcium release from sustained to transient. Cell death was accompanied by plasma-membrane disruption, loss of mitochondrial membrane-potential and caspase-9/caspase-3 activation. PPARgamma-mediated apoptosis was unaffected following pre-treatment with PPARgamma antagonist T0070907 and was strongly attenuated by store-operated calcium channel (SOC) inhibitors 2-APB and SKF-96365.. Our results provide a mechanistic basis for the ability of some PPAR agonists to induce death in NHU cells and demonstrate that apoptosis is mediated via PPAR-independent mechanisms, involving intracellular calcium changes, activation of SOCs and induction of the mitochondrial apoptotic pathway. Topics: Apoptosis; Calcium; Calcium Channels; Caspase 3; Caspase 9; Cell Division; Cells, Cultured; Chromans; Epithelial Cells; Extracellular Signal-Regulated MAP Kinases; Fenofibrate; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Membrane Potential, Mitochondrial; Oxazines; p38 Mitogen-Activated Protein Kinases; Peroxisome Proliferator-Activated Receptors; Phenoxyacetates; Phenylpropionates; Rosiglitazone; Thiazolidinediones; Troglitazone; Urothelium | 2009 |