Thus, the anti-tumour effects noted by inhibiting mTOR may be related to antiproliferative effects within tumour cells as well endothelial cells. WH-4-023 price Upstream effectors that signal through mTOR may up-regulate mTOR gene. Wu X et al (2004) showed that a specific inhibitor of PI3 kinase enzyme activity, Ly294002, potently suppressed the invasive properties of three highly invasive bladder tumour cell lines and 55% of primary tumours from patients with bladder check details cancer had markedly high levels of phosphorylated Akt [26]. Thus, the inhibition of mTOR may inhibit abnormal cell proliferation, tumour angiogenesis, and abnormal cell metabolism and potentially enhance
the efficacy of other cancer treatments. The biological mechanisms responsible for anti-proliferative
effect of sirolimus and the role of PI3K-Akt-mTOR pathway are under investigation [27]. Tanaka and Grossman (2003) demonstrate that PTEN can induce growth suppression and increase sensitivity to doxorubicin in bladder cancer cells and suggest that the PTEN gene and its pathways can be therapeutic targets for bladder cancer. To emphasize that, no results have been yet published on the activity of mTOR inhibitors against T24, or other, bladder cancer cell lines. Luan FL et al. (2002) showed that, sirolimus treatment alone, or with cyclosporine, prolonged the survival of mice inoculated with renal cancer cells or T24 human bladder cancer cells [28]. This is an indirect assumption of sirolimus effect against T24. The present study is the first address this issue. In the other hand, our team observed similar results, when we studied the PCI-34051 effects of sirolimus in chemical induced urothelial cancers in ICR mice (data submitted). Sirolimus has been shown to inhibit the proliferation of various tumour cell lines including rhabdomyosarcoma, neuroblastoma, glioblastoma, small cell lung cancer, osteosarcoma, pancreatic cancer, breast cancer, prostate cancer, murine melanoma, leukaemia, and B-cell lymphoma [29–33]. Sirolimus enhances the anti-tumour effect of gemcitabine [34]. Now we intend to verify the efficacy
of sirolimous mTOR inhibition, in other bladder cancer cell lines (5637, HT1376 and MC). Clinical results show that mTOR inhibitors are well tolerated and may induce prolonged stable disease and tumour regression in cancer patients [24]. Urgent research is needed to evaluate the real place of sirolimus STK38 or similar drugs in urothelial bladder cancer therapeutic. Conclusion Sirolimus inhibits T24 bladder cancer cell proliferation and decrease cell viability including in clinical dose, therefore should be considered to be a promising agents against bladder cancer. However, more positive data will be necessary. References 1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ: Cancer statistics 2007. CA Cancer J Clin 2007, 57: 43–66.CrossRefPubMed 2. Parkin DM, Bray F, Ferlay J, Pisani P: Global Cancer Statistics, 2002. CA Cancer J Clin 2005, 55: 74–108.CrossRefPubMed 3.