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.
Highlights
Since ketogenic diet (KD) was established in the 1920s to treat epilepsy [1], it has been under investigation for many years as a potential therapy for numerous other diseases, such as Parkinson’s disease, Alzheimer’s disease, acne, and diabetes [2,3,4,5,6]
It would be interesting to investigate metabolites locally in tumor tissue, this has its limitations as tumor tissue is frequently heterogeneous, and the microenviroment consisting of tumor-associated macrophages (TAMs), tumor associated fibroblasts (TAFs), and the vascular system would contribute to the data
We could show that long-chain triglycerides (LCT)-MCT8 diet can shift a derailed plasma metabolome induced by breast cancer xenografts under chemotherapy back to the one of healthy mice
Summary
Since ketogenic diet (KD) was established in the 1920s to treat epilepsy [1], it has been under investigation for many years as a potential therapy for numerous other diseases, such as Parkinson’s disease, Alzheimer’s disease, acne, and diabetes [2,3,4,5,6]. KD reduces the levels of insulin and insulin-like growth factor (IGF-1) [7]. In the view of tumor formation and growth, the most important functions of the growth factors of the IGF family are that they enhance both cell proliferation and escape from apoptosis [8]. In the long tradition of applying this diet, various forms have been developed mainly differing in the fat:carbohydrate:protein ratio and in the type of fat used. An alternative to the traditional KD is, for example, a KD supplemented with medium-chain triglyceride (MCT). Compared to long-chain triglycerides (LCT), MCTs are more rapidly absorbed into the bloodstream and oxidized for energy delivery because of their ability to passively diffuse through membranes. Adding MCTs to a KD might allow a less strict diet [13,14]
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