Abstract
Bladder cancer is a common malignancy worldwide. Despite the increased use of cisplatin-based combination therapy, the outcomes for patients with advanced disease remain poor. Recently, altered activation of the PI3K/ Akt/mTOR pathway has been associated with reduced patient survival and advanced stage of bladder cancer, making its upstream or downstream components attractive targets for therapeutic intervention. In the present study, we showed that treatment with DTCM-glutaramide, a piperidine that targets PDK1, results in reduced proliferation, diminished cell migration and G1 arrest in 5637 and T24 bladder carcinoma cells. Conversely, no apoptosis, necrosis or autophagy were detected after treatment, suggesting that reduced cell numbers in vitro are a result of diminished proliferation rather than cell death. Furthermore previous exposure to 10 μg/ml DTCM- glutarimide sensitized both cell lines to ionizing radiation. Although more studies are needed to corroborate our findings, our results indicate that PDK1 may be useful as a therapeutic target to prevent progression and abnormal tissue dissemination of urothelial carcinomas.
Highlights
Carcinoma of the urinary bladder is a common cancer that accounts for approximately 300,000 new cases each year (Jemal et al, 2008)
Altered activation of the PI3K/ Akt/Mammalian target of rapamycin (mTOR) pathway has been associated with reduced patient survival and advanced stage of bladder cancer, making its upstream or downstream components attractive targets for therapeutic intervention
Altered mTOR pathway activity is associated with reduced patient survival and advanced stage in bladder carcinoma (Hansel et al, 2010; Sun et al, 2011), the phosphatidylinositol-dependent kinase 1 (PDK1)/ Akt pathway is believed to be an attractive target for therapeutic intervention
Summary
Carcinoma of the urinary bladder is a common cancer that accounts for approximately 300,000 new cases each year (Jemal et al, 2008). Approximately 80% of patients recur in 1 to 2 years and despite radical cystectomy and systemic therapy, a substantial proportion of cases progress to invasive tumors and die from metastasis within 12-15 months (Kaufman, 2006). The phosphatidylinositol 3-kinase PI3K is an essential enzyme in signal transduction from various stimuli to downstream pathways involved in diverse responses associated with growth, proliferation and survival. Altered mTOR pathway activity is associated with reduced patient survival and advanced stage in bladder carcinoma (Hansel et al, 2010; Sun et al, 2011), the PDK1/ Akt pathway is believed to be an attractive target for therapeutic intervention. We present evidence of the antiproliferative effects of the piperidine compound DTCM-glutarimide on 5637 and T24 cells offering a rationale for a therapeutic targeting in bladder cancer
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