Đang chuẩn bị nút TẢI XUỐNG, xin hãy chờ
Tải xuống
Tuyển tập các báo cáo nghiên cứu về hóa học được đăng trên tạp chí sinh học đề tài : Characterization and targeting of phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in renal cell cancer | Elfiky et al. Journal of Translational Medicine 2011 9 133 http www.translational-medicine.eom content 9 1 133 JOURNAL OF TRANSLATIONAL MEDICINE RESEARCH Open Access Characterization and targeting of phosphatidylinositol-3 kinase PI3K and mammalian target of rapamycin mTOR in renal cell cancer Aymen A Elfiky1 Saadia A Aziz2 Patricia J Conrad2 Summar Siddiqui3 Wolfgang Hackl4 Michel Maira4 Camp L Robert3 and Harriet M Kluger2 Abstract Background PI3K and mTOR are key components of signal transduction pathways critical for cell survival. Numerous PI3K inhibitors have entered clinical trials while mTOR is the target of approved drugs for metastatic renal cell carcinoma RCC . We characterized expression of p85 and p110a PI3K subunits and mTOR in RCC specimens and assessed pharmacologic co-targeting of these molecules in vitro. Methods We employed tissue microarrays containing 330 nephrectomy cases using a novel immunofluorescencebased method of Automated Quantitative Analysis AQUA of in situ protein expression. In RCC cell lines we assessed synergism between PI3K and mTOR inhibitors and activity of NVP-BEZ235 which co-targets PI3K and mTOR. Results p85 expression was associated with high stage and grade P 0.0001 for both . High p85 and high mTOR expression were strongly associated with decreased survival and high p85 was independently prognostic on multivariable analysis. Strong co-expression of both PI3K subunits and mTOR was found in the human specimens. The PI3K inhibitor LY294002 and rapamycin were highly synergistic in all six RCC cell lines studied. Similar synergism was seen with all rapamycin concentrations used. NVP-BEZ235 inhibited RCC cell growth in vitro with IC50s in the low hM range and resultant PARP cleavage. Conclusions High PI3K and mTOR expression in RCC defines populations with decreased survival suggesting that they are good drug targets in RCC. These targets tend to be co-expressed and co-targeting these molecules is synergistic. NVP-BEZ235 is .
