Experimentelle Untersuchungen zur Verstoffwechselung von Ketonkörpern und Laktat durch Tumorzellen des Gastrointestinaltrakts

Zusammenfassung

Fragestellung: Die Auswirkungen einer ketogenen Diät auf das Wachstum solider Tumoren werden aktuell kontrovers diskutiert. Aus diesem Grund wurde in vitro untersucht, bei welchen Sauerstoffkonzentrationen Tumorzellen Ketonkörper (β-Hydroxybutyrat) und die beiden Metabolite Glukose und Laktat, die auch bei einer ketogenen Diät vorkommen, verstoffwechseln. Zudem wurde exemplarisch das Tumorwachstum unter einer standardisierten ketogenen Diät im Tiermodell überprüft.

Material und Methodik: Konfluente Kulturen von 6 humanen gastrointestinalen Tumorzelllinien wurden in vitro bei 21 % und 1 % Sauerstoff untersucht. Glukose, Laktat und β-Hydroxybutyrat wurden mit Standardenzymassays bestimmt. Mit einer standardisierten ketogenen Diät wurde in Kleinnagern eine physiologische Ketose ausgelöst und durch subkutane Injektion von Tumorzellen das Wachstum solider Tumoren induziert.

Ergebnisse: Kulturen der 6 Tumorzelllinien verstoffwechseln Ketonkörper und Laktat bei 21 %, nicht aber bei 1 % Sauerstoff; dagegen wird Glukose bei beiden Sauerstoffkonzentrationen metabolisiert. Stehen Tumorzellen bei 21 % Sauerstoff die beiden Energieträger Glukose und Laktat gleichzeitig zur Verfügung, wird zuerst Glukose und anschließend Laktat verstoffwechselt. Unter einer ketogenen Diät entwickeln Mäuse eine physiologische Ketose mit signifikant erhöhten Ketonkörperspiegeln. Die Tumoren dieser Mäuse weisen verringerte intratumorale Laktatspiegel und ein verzögertes Wachstum auf.

Schlussfolgerung: Die In-vitro-Daten dieser experimentellen Arbeit unterstützen das Konzept, dass in vivo der Stoffwechsel solider Tumoren durch die lokale Sauerstoffversorgung wesentlich beeinflusst wird. Sauerstoffkonzentrationen von 1 %, die regelhaft in soliden Tumoren vorzufinden sind (Tumorhypoxie), reichen in vitro nicht aus, damit gastrointestinale Tumorzellen Ketonkörper und Laktat verstoffwechseln; im Gegensatz zur Glukose. Um Tumorzellen in Hypoxie zum Absterben zu bringen, sollte bei ihnen daher der Glukosestoffwechsel selektiv gehemmt und zusätzlich das Glukoseangebot durch diätetische Maßnahmen eingeschränkt werden.

Abstract

Purpose: The effect of a ketogenic diet on tumour growth is currently controversial. For this study we analysed tumour cells in vitro to determine what level of oxygen is required for the oxidative degradation of ketone bodies (β-hydroxybutyrate) and the metabolites glucose and lactate that are also present in a ketogenic diet. In addition, tumour growth was examined under a standard ketogenic diet in an animal model.

Material and Methods: Six different gastrointestinal tumour cell lines grown to confluence were investigated in vitro for their metabolic properties at 21 % and 1 % oxygen. Concentrations of glucose, lactate, and β-hydroxybutyrate were quantified using standard enzymatic assays. A ketosis was induced in nude mice via a standardised ketogenic diet and tumour growth was induced by subcutaneously injected tumour cells.

Results: Cell cultures of the 6 tumour cell lines were able to metabolize ketone bodies as well as lactate at 21 % oxygen, but not at 1 %. Glucose, in contrast, was metabolized at both oxygen concentrations by all 6 tumour cell lines. The data indicate that tumour cells with access to both glucose and lactate at 21 % oxygen, consume glucose first and only when glucose is exhausted, do they start to metabolise lactate. Mice fed a ketogenic diet represent a clear physiological ketosis with elevated blood ketone levels. Tumours in the ketogenic diet group grew slower and had lower intratumoral lactate levels in comparison to tumours in the standard diet group.

Conclusion: The in vitro data presented support the concept that metabolism in solid tumours is significantly influenced by the local oxygenation. Oxygen concentrations of 1 %, usually found in solid tumours (tumour hypoxia), are insufficient for the in vitro metabolization of ketone bodies and lactate in tumour cell lines, in contrast to glucose that is metabolized under these conditions. Therefore, a therapeutic approach that targets the tumour cell energy metabolism under hypoxic conditions must inhibit glucose metabolism pharmacologically with decreased glucose supply, e. g. via dietary interventions.

Schlüsselwörter

ketogene Diät - Ketonkörper - Zuckerstoffwechsel - Hypoxie - Tumorwachstum

Keywords

ketogenic diet - ketone bodies - glucose metabolism - hypoxia - tumour growth

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