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10.1007/s00280-011-1684-y http://scihub22266oqcxt.onion/10.1007/s00280-011-1684-y C4562405!4562405 !21644050     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=21644050 &cmd=llinks): Failed to open stream: HTTP request failed! 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Evaluating rational non-cross-resistant combination therapy in advanced clear cell renal cell carcinoma: combined mTOR and AKT inhibitor therapy |pdf=|usr=}}{{21644050 }} gab.com Text Evaluating rational non-cross-resistant combination therapy in advanced clear cell renal cell carcinoma: combined mTOR and AKT inhibitor therapy JO: Cancer Chemother Pharmacol http://www.kidney.de/pget.php?&tw=1&pmid=21644050 #FOAvip PURPOSE: Inhibition of the mammalian target of rapamycin (mTOR), a regulator of hypoxia inducible factor (HIF), is an established therapy for advanced renal cell cancer (RCC). Inhibition of mTOR results in compensatory AKT activation, a likely resistance mechanism. We evaluated whether addition of the Akt inhibitor perifosine to the mTOR inhibitor rapamycin would synergistically inhibit RCC. METHODS: Select RCC cell lines were studied [786-O, A498 (VHL mutant), CAKI-1 (VHL wild type), and 769-P (VHL methylated)] with single agent and combination therapy. Growth inhibition was assessed by MTT and cell cycling by flow cytometry. Phospho-AKT (S473) and HIF-2? were assessed by Western blot. Total RNA was isolated from 786-O cells subjected to single agent and combination treatments. In these cells, genome-wide expression profiles were assessed, and real-time PCR was used to confirm a limited set of expression results. RESULTS: Three out of four cell lines (CAKI-1, 769-P, and 786-O) were sensitive to single-agent perifosine with 50% inhibitory concentrations ranging from 5 to 10 ?M. Perifosine blocked phosphorylation of AKT induced by rapamycin and inhibited HIF-2? expression in 786-O and CAKI-1. Combined treatment resulted in sub-additive growth inhibition. GeneChip analysis and pathway modeling revealed inhibition of the IL-8 pathway by these agents, concomitant with up-regulation of the KLF2 gene, a known suppressor of HIF1?. CONCLUSIONS: Perifosine is active in select RCC lines, abrogating the induction of AKT phosphorylation mediated by mTOR inhibition. Combined mTOR and AKT inhibition resulted in the modulation of pro-angiogenesis pathways, providing a basis for future investigations. Twit Text FOAVip Evaluating rational non-cross-resistant combination therapy in advanced clear cell renal cell carcinoma: combined mTOR and AKT inhibitor therapy ????Cancer Chemother Pharmacol http://www.kidney.de/pget.php?&tw=1&pmid=21644050 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=21644050 #FOAvip English Wikipedia <ref>{{Cite pmid|21644050 }}</ref> Evaluating rational non-cross-resistant combination therapy in advanced clear cell renal cell carcinoma: combined mTOR and AKT inhibitor therapy #MMPMID21644050 Holland WS ; Tepper CG ; Pietri JE ; Chinn DC ; Gandara DR ; Mack PC ; Lara PN Jr Cancer Chemother Pharmacol 2012[Jan]; 69 (1 ): 185-94 PMID21644050 show ga PURPOSE: Inhibition of the mammalian target of rapamycin (mTOR), a regulator of hypoxia inducible factor (HIF), is an established therapy for advanced renal cell cancer (RCC). Inhibition of mTOR results in compensatory AKT activation, a likely resistance mechanism. We evaluated whether addition of the Akt inhibitor perifosine to the mTOR inhibitor rapamycin would synergistically inhibit RCC. METHODS: Select RCC cell lines were studied [786-O, A498 (VHL mutant), CAKI-1 (VHL wild type), and 769-P (VHL methylated)] with single agent and combination therapy. Growth inhibition was assessed by MTT and cell cycling by flow cytometry. Phospho-AKT (S473) and HIF-2? were assessed by Western blot. Total RNA was isolated from 786-O cells subjected to single agent and combination treatments. In these cells, genome-wide expression profiles were assessed, and real-time PCR was used to confirm a limited set of expression results. RESULTS: Three out of four cell lines (CAKI-1, 769-P, and 786-O) were sensitive to single-agent perifosine with 50% inhibitory concentrations ranging from 5 to 10 ?M. Perifosine blocked phosphorylation of AKT induced by rapamycin and inhibited HIF-2? expression in 786-O and CAKI-1. Combined treatment resulted in sub-additive growth inhibition. GeneChip analysis and pathway modeling revealed inhibition of the IL-8 pathway by these agents, concomitant with up-regulation of the KLF2 gene, a known suppressor of HIF1?. CONCLUSIONS: Perifosine is active in select RCC lines, abrogating the induction of AKT phosphorylation mediated by mTOR inhibition. Combined mTOR and AKT inhibition resulted in the modulation of pro-angiogenesis pathways, providing a basis for future investigations. |Antineoplastic Combined Chemotherapy Protocols/administration & dosage/*pharmacology [MESH] |Carcinoma, Renal Cell/*drug therapy/pathology [MESH] |Cell Line, Tumor [MESH] |Drug Resistance, Neoplasm [MESH] |Drug Synergism [MESH] |Gene Expression Regulation, Neoplastic/drug effects [MESH] |Humans [MESH] |Inhibitory Concentration 50 [MESH] |Interleukin-8/drug effects/genetics [MESH] |Kidney Neoplasms/*drug therapy/pathology [MESH] |Neovascularization, Pathologic/drug therapy [MESH] |Oligonucleotide Array Sequence Analysis [MESH] |Phosphorylation/drug effects [MESH] |Phosphorylcholine/administration & dosage/analogs & derivatives [MESH] |Proto-Oncogene Proteins c-akt/antagonists & inhibitors [MESH] |Sirolimus/administration & dosage [MESH]Evaluating rational non-cross-resistant combination therapy in advance(epmc).pdf DeepDyve Pubget Overpricing