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Rapamycin as mammalian target of rapamycin inhibitor and 5\u2010aminoimidazole\u20104\u2010carboxamide\u2010riboside (<jats:styled-content style=\"fixed-case\">AICAR<\/jats:styled-content>) as <jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content> activator are used separately to treat cancer patients. In the current study, the possible additive effect of drug combinations in reducing kidney tumorigenesis was investigated. Treatment with drug combinations significantly decreased cell proliferation, increased cell apoptosis, and abolished Akt phosphorylation and <jats:styled-content style=\"fixed-case\">HIF<\/jats:styled-content>\u20102\u03b1 expression in renal cell carcinoma cells, including primary cells isolated from kidney cancer patients. Significant decreases in cell migration and invasion were detected using drug combinations. Drug combinations effectively abolished binding of <jats:styled-content style=\"fixed-case\">HIF<\/jats:styled-content>\u20102\u03b1 to the Akt promoter and effected formation of the <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content>\u2010protein complex in nuclear extracts from 786\u2010O cells, as demonstrated using electromobility shift assay and examination of Akt promoter activity. Importantly, we tested the effect of each drug and the combined drugs on kidney tumor size in the nude mouse model. Our data show that treatment with rapamycin, <jats:styled-content style=\"fixed-case\">AICAR<\/jats:styled-content>, and rapamycin+<jats:styled-content style=\"fixed-case\">AICAR<\/jats:styled-content> decreased tumor size by 38%, 36%, and 80%, respectively, suggesting that drug combinations have an additive effect in reducing tumor size compared with use of each drug alone. Drug combinations effectively decreased cell proliferation, increased apoptotic cells, and significantly decreased p\u2010Akt, <jats:styled-content style=\"fixed-case\">HIF<\/jats:styled-content>\u20102\u03b1, and vascular endothelial growth factor expression in tumor kidney tissues from mice. These results show for the first time that drug combinations are more effective than single drugs in reducing kidney tumor progression. This study provides important evidence that may lead to the initiation of pre\u2010clinical trials in patients with kidney cancer.<\/jats:p>","DOI":"10.1002\/1878-0261.12370","type":"journal-article","created":{"date-parts":[[2018,8,14]],"date-time":"2018-08-14T21:09:29Z","timestamp":1534280969000},"page":"1917-1934","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Preclinical evidence of the enhanced effectiveness of combined rapamycin and <scp>AICAR<\/scp> in reducing kidney cancer"],"prefix":"10.1002","volume":"12","author":[{"given":"Sitai","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Cell Systems &amp; Anatomy University of Texas Health Science Center at San Antonio TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward A.","family":"Medina","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine University of Texas 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