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Open AccessArticle

Untargeted Metabolomics Reveals Molecular Effects of Ketogenic Diet on Healthy and Tumor Xenograft Mouse Models

1
Bioanalytical Research Laboratories, Department of Biosciences and Cancer Cluster Salzburg, University of Salzburg, Hellbrunnerstraße 34, 5020 Salzburg, Austria
2
Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, 5020 Salzburg, Austria
3
Applied Bioinformatics, Department of Computer Science, University of Tübingen, 72076 Tübingen, Germany
4
Institute for Bioinformatics and Medical Informatics, University of Tübingen, Sand 14, 72076 Tübingen, Germany
5
Institute for Translational Bioinformatics, University Hospital Tübingen, 72076 Tübingen, Germany
6
Biomolecular Interactions, Max Planck Institute for Developmental Biology, Max-Planck-Ring 5, 72076 Tübingen, Germany
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(16), 3873; https://doi.org/10.3390/ijms20163873
Received: 25 June 2019 / Revised: 5 August 2019 / Accepted: 7 August 2019 / Published: 8 August 2019
(This article belongs to the Special Issue The Effects of Ketones on Metabolic Function)
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PDF [2923 KB, uploaded 8 August 2019]
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Abstract

The application of ketogenic diet (KD) (high fat/low carbohydrate/adequate protein) as an auxiliary cancer therapy is a field of growing attention. KD provides sufficient energy supply for healthy cells, while possibly impairing energy production in highly glycolytic tumor cells. Moreover, KD regulates insulin and tumor related growth factors (like insulin growth factor-1, IGF-1). In order to provide molecular evidence for the proposed additional inhibition of tumor growth when combining chemotherapy with KD, we applied untargeted quantitative metabolome analysis on a spontaneous breast cancer xenograft mouse model, using MDA-MB-468 cells. Healthy mice and mice bearing breast cancer xenografts and receiving cyclophosphamide chemotherapy were compared after treatment with control diet and KD. Metabolomic profiling was performed on plasma samples, applying high-performance liquid chromatography coupled to tandem mass spectrometry. Statistical analysis revealed metabolic fingerprints comprising numerous significantly regulated features in the group of mice bearing breast cancer. This fingerprint disappeared after treatment with KD, resulting in recovery to the metabolic status observed in healthy mice receiving control diet. Moreover, amino acid metabolism as well as fatty acid transport were found to be affected by both the tumor and the applied KD. Our results provide clear evidence of a significant molecular effect of adjuvant KD in the context of tumor growth inhibition and suggest additional mechanisms of tumor suppression beyond the proposed constrain in energy supply of tumor cells. View Full-Text
Keywords: ketogenic diet; breast cancer; xenograft; untargeted metabolomics; HPLC-MS; reversed phase chromatography; hydrophilic liquid interaction chromatography ketogenic diet; breast cancer; xenograft; untargeted metabolomics; HPLC-MS; reversed phase chromatography; hydrophilic liquid interaction chromatography
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Licha, D.; Vidali, S.; Aminzadeh-Gohari, S.; Alka, O.; Breitkreuz, L.; Kohlbacher, O.; Reischl, R.J.; Feichtinger, R.G.; Kofler, B.; Huber, C.G. Untargeted Metabolomics Reveals Molecular Effects of Ketogenic Diet on Healthy and Tumor Xenograft Mouse Models. Int. J. Mol. Sci. 2019, 20, 3873.

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