Abstract
BackgroundCiglitazone belongs to the thiazolidinediones class of antidiabetic drug family and is a high-affinity ligand for the Peroxisome Proliferator-Activated Receptor γ (PPARγ). Apart from its antidiabetic activity, this molecule shows antineoplastic effectiveness in numerous cancer cell lines.Methodology/Principal FindingsUsing RT4 (derived from a well differentiated grade I papillary tumor) and T24 (derived from an undifferentiated grade III carcinoma) bladder cancer cells, we investigated the potential of ciglitazone to induce apoptotic cell death and characterized the molecular mechanisms involved. In RT4 cells, the drug induced G2/M cell cycle arrest characterized by an overexpression of p53, p21waf1/CIP1 and p27Kip1 in concomitance with a decrease of cyclin B1. On the contrary, in T24 cells, it triggered apoptosis via extrinsic and intrinsic pathways. Cell cycle arrest and induction of apoptosis occurred at high concentrations through PPARγ activation-independent pathways. We show that in vivo treatment of nude mice by ciglitazone inhibits high grade bladder cancer xenograft development. We identified a novel mechanism by which ciglitazone kills cancer cells. Ciglitazone up-regulated soluble and membrane-bound TRAIL and let TRAIL-resistant T24 cells to respond to TRAIL through caspase activation, death receptor signalling pathway and Bid cleavage. We provided evidence that TRAIL-induced apoptosis is partially driven by ciglitazone-mediated down-regulation of c-FLIP and survivin protein levels through a proteasome-dependent degradation mechanism.Conclusions/SignificanceTherefore, ciglitazone could be clinically relevant as chemopreventive or therapeutic agent for the treatment of TRAIL-refractory high grade urothelial cancers.
Highlights
Urothelial carcinoma of the bladder accounts for,5% of all cancer deaths in humans
The present study reported the effects of ciglitazone on RT4 and T24 bladder cancer cell lines
Depending on differentiated state of the cells, we showed that ciglitazone individual treatment induced G2/M phase cell cycle arrest but triggered apoptosis only in T24 high grade bladder cancer cells through Peroxisome Proliferator-Activated Receptor c (PPARc) activation-independent mechanisms
Summary
Urothelial carcinoma of the bladder accounts for ,5% of all cancer deaths in humans. The majority of bladder tumors (75%) are non muscle-invasive at diagnosis and after local surgical therapy, have a high risk of recurrence and a propensity to progress in grade or stage [1]. Muscle invasive tumors (25%) have a poorer prognosis [2] since 50% of patients will relapse with metastatic disease within 2 years of treatment. Developing novel effective chemotherapeutic regimens with fewer side effects are definitely needed to decrease the morbidity and the mortality of urothelial carcinoma. Thiazolidinediones (TZD), including rosiglitazone, troglitazone, pioglitazone and ciglitazone are a class of insulin-sensitizing drugs. Ciglitazone belongs to the thiazolidinediones class of antidiabetic drug family and is a high-affinity ligand for the Peroxisome Proliferator-Activated Receptor c (PPARc). Apart from its antidiabetic activity, this molecule shows antineoplastic effectiveness in numerous cancer cell lines
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