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Preclinical evidence of the enhanced effectiveness of combined rapamycin and AICAR in reducing kidney cancer

Loss of Von Hippel‐Lindau in renal carcinoma cells results in upregulation of the activity of hypoxia‐inducible factor (HIF‐α), a major transcription factor involved in kidney cancer. Rapamycin as mammalian target of rapamycin inhibitor and 5‐aminoimidazole‐4‐carboxamide‐riboside (AICAR) as AMPK act...

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Autores principales: Liang, Sitai, Medina, Edward A., Li, Boajie, Habib, Samy L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210038/
https://www.ncbi.nlm.nih.gov/pubmed/30107094
http://dx.doi.org/10.1002/1878-0261.12370
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author Liang, Sitai
Medina, Edward A.
Li, Boajie
Habib, Samy L.
author_facet Liang, Sitai
Medina, Edward A.
Li, Boajie
Habib, Samy L.
author_sort Liang, Sitai
collection PubMed
description Loss of Von Hippel‐Lindau in renal carcinoma cells results in upregulation of the activity of hypoxia‐inducible factor (HIF‐α), a major transcription factor involved in kidney cancer. Rapamycin as mammalian target of rapamycin inhibitor and 5‐aminoimidazole‐4‐carboxamide‐riboside (AICAR) as AMPK 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 HIF‐2α 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 HIF‐2α to the Akt promoter and effected formation of the DNA‐protein complex in nuclear extracts from 786‐O 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, AICAR, and rapamycin+AICAR 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‐Akt, HIF‐2α, 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‐clinical trials in patients with kidney cancer.
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spelling pubmed-62100382018-11-08 Preclinical evidence of the enhanced effectiveness of combined rapamycin and AICAR in reducing kidney cancer Liang, Sitai Medina, Edward A. Li, Boajie Habib, Samy L. Mol Oncol Research Articles Loss of Von Hippel‐Lindau in renal carcinoma cells results in upregulation of the activity of hypoxia‐inducible factor (HIF‐α), a major transcription factor involved in kidney cancer. Rapamycin as mammalian target of rapamycin inhibitor and 5‐aminoimidazole‐4‐carboxamide‐riboside (AICAR) as AMPK 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 HIF‐2α 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 HIF‐2α to the Akt promoter and effected formation of the DNA‐protein complex in nuclear extracts from 786‐O 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, AICAR, and rapamycin+AICAR 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‐Akt, HIF‐2α, 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‐clinical trials in patients with kidney cancer. John Wiley and Sons Inc. 2018-10-12 2018-11 /pmc/articles/PMC6210038/ /pubmed/30107094 http://dx.doi.org/10.1002/1878-0261.12370 Text en © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Liang, Sitai
Medina, Edward A.
Li, Boajie
Habib, Samy L.
Preclinical evidence of the enhanced effectiveness of combined rapamycin and AICAR in reducing kidney cancer
title Preclinical evidence of the enhanced effectiveness of combined rapamycin and AICAR in reducing kidney cancer
title_full Preclinical evidence of the enhanced effectiveness of combined rapamycin and AICAR in reducing kidney cancer
title_fullStr Preclinical evidence of the enhanced effectiveness of combined rapamycin and AICAR in reducing kidney cancer
title_full_unstemmed Preclinical evidence of the enhanced effectiveness of combined rapamycin and AICAR in reducing kidney cancer
title_short Preclinical evidence of the enhanced effectiveness of combined rapamycin and AICAR in reducing kidney cancer
title_sort preclinical evidence of the enhanced effectiveness of combined rapamycin and aicar in reducing kidney cancer
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210038/
https://www.ncbi.nlm.nih.gov/pubmed/30107094
http://dx.doi.org/10.1002/1878-0261.12370
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