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

Sitai Liang, Edward Medina, Boajie Li, Samy L Habib

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1917-1934
Number of pages18
JournalMolecular Oncology
Volume12
Issue number11
DOIs
StatePublished - Nov 1 2018

Fingerprint

Kidney Neoplasms
Drug Combinations
Sirolimus
Kidney
Neoplasms
Renal Cell Carcinoma
Pharmaceutical Preparations
Cell Proliferation
AMP-Activated Protein Kinases
acadesine
Nude Mice
Vascular Endothelial Growth Factor A
Cell Movement
Carcinogenesis
Transcription Factors
Up-Regulation
Phosphorylation
Clinical Trials
Apoptosis
DNA

Keywords

  • 5-aminoimidazole-4-carboxamide-riboside (AICAR)
  • hypoxia-inducible factor (HIF-α)
  • kidney cancer
  • rapamycin
  • Von Hippel-Lindau

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

Cite this

Preclinical evidence of the enhanced effectiveness of combined rapamycin and AICAR in reducing kidney cancer. / Liang, Sitai; Medina, Edward; Li, Boajie; Habib, Samy L.

In: Molecular Oncology, Vol. 12, No. 11, 01.11.2018, p. 1917-1934.

Research output: Contribution to journalArticle

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abstract = "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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