Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity

Abstract

Background Growing evidence supports the use of low-carbohydrate/high-fat ketogenic diets as an adjunctive cancer therapy. However, it is unclear which genetic, metabolic, or immunological factors contribute to the beneficial effect of ketogenic diets. Therefore, we investigated the effect of ketogenic diets on the progression and metabolism of genetically and metabolically heterogeneous melanoma xenografts, as well as on the development of melanoma metastases in mice with a functional immune system. Methods Mice bearing BRAF mutant, NRAS mutant, and wild-type melanoma xenografts as well as mice bearing highly metastatic melanoma allografts were fed with a control diet or ketogenic diets, differing in their triglyceride composition, to evaluate the effect of ketogenic diets on tumor growth and metastasis. We performed an in-depth targeted metabolomics analysis in plasma and xenografts to elucidate potential antitumor mechanisms in vivo. Results We show that ketogenic diets effectively reduced tumor growth in immunocompromised mice bearing genetically and metabolically heterogeneous human melanoma xenografts. Furthermore, the ketogenic diets exerted a metastasis-reducing effect in the immunocompetent syngeneic melanoma mouse model. Targeted analysis of plasma and tumor metabolomes revealed that ketogenic diets induced distinct changes in amino acid metabolism. Interestingly, ketogenic diets reduced the levels of alpha-amino adipic acid, a biomarker of cancer, in circulation to levels observed in tumor-free mice. Additionally, alpha-amino adipic acid was reduced in xenografts by ketogenic diets. Moreover, the ketogenic diets increased sphingomyelin levels in plasma and the hydroxylation of sphingomyelins and acylcarnitines in tumors. Conclusions Ketogenic diets induced antitumor effects toward melanoma regardless of the tumors´ genetic background, its metabolic signature, and the host immune status. Moreover, ketogenic diets simultaneously affected multiple metabolic pathways to create an unfavorable environment for melanoma cell proliferation, supporting their potential as a complementary nutritional approach to melanoma therapy.

Anti-tumor effects of ketogenic diets and their synergism with other treatments in mice: Bayesian evidence synthesis of 1755 individual mouse survival data

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Ketogenic diet in cancer management

“…]. Moreover, Weber et al [40] have reported the anticancer effect of KD in melanoma. The metabolomics analysis of the ketogenic diet-treated group exhibited a low level of alpha-amino adipic acid, a biomarker of cancer, and mediated the hydroxylation of sphingomyelin and acylcarnitines in tumor tissue.…”

Take metabolic heterogeneity into consideration when applying dietary interventions to cancer therapy: A review

“…However, when melanoma cells harbor a BRAF V600E mutation, they become resistant to KD, as acetoacetate, one metabolite elevated under KD, can augment BRAF signaling [ 22 , 121 ]. BRAF V600E mutation underlying the tumor-promoting effects of KD in melanoma was argued by another animal study, in which KD slowed melanoma growth in vivo regardless of genetic background [ 122 ]. The authors attributed this difference to two reasons: first, the dietary regimens used by two studies differed in their ketogenic ability; second, the timing of KD administration was also different: one study started the KD intervention once the xenografts had reached a measurable size, while the other study started the KD intervention 1 week before tumor initiation [ 122 ].…”

“…BRAF V600E mutation underlying the tumor-promoting effects of KD in melanoma was argued by another animal study, in which KD slowed melanoma growth in vivo regardless of genetic background [ 122 ]. The authors attributed this difference to two reasons: first, the dietary regimens used by two studies differed in their ketogenic ability; second, the timing of KD administration was also different: one study started the KD intervention once the xenografts had reached a measurable size, while the other study started the KD intervention 1 week before tumor initiation [ 122 ]. These differences in study design may significantly influence the response, which needs to be addressed in further studies.…”