A ketogenic diet supplemented with medium-chain triglycerides enhances the anti-tumor and anti-angiogenic efficacy of chemotherapy on neuroblastoma xenografts in a CD1-nu mouse model

Abstract

Neuroblastoma (NB) is a pediatric malignancy characterized by a marked reduction in aerobic energy metabolism. Recent preclinical data indicate that targeting this metabolic phenotype by a ketogenic diet (KD), especially in combination with calorie restriction, slows tumor growth and enhances metronomic cyclophosphamide (CP) therapy of NB xenografts. Because calorie restriction would be contraindicated in most cancer patients, the aim of the present study was to optimize the KD such that the tumors are sensitized to CP without the need of calorie restriction. In a NB xenograft model, metronomic CP was combined with KDs of different triglyceride compositions and fed to CD1-nu mice ad libitum. Metronomic CP in combination with a KD containing 8-carbon medium-chain triglycerides exerted a robust anti-tumor effect, suppressing growth and causing a significant reduction of tumor blood-vessel density and intratumoral hemorrhage, accompanied by activation of AMP-activated protein kinase in NB cells. Furthermore, the KDs caused a significant reduction in the serum levels of essential amino acids, but increased those of serine, glutamine and glycine. Our data suggest that targeting energy metabolism by a modified KD may be considered as part of a multimodal treatment regimen to improve the efficacy of classic anti-NB therapy.

Modulation of Cellular Biochemistry, Epigenetics and Metabolomics by Ketone Bodies. Implications of the Ketogenic Diet in the Physiology of the Organism and Pathological States

“…Moreover, the decrease in insulin level that accompanies the indicated ketonemic conditions correlates with a decrease in insulin-like growth factors, which promotes the proliferation of cancer cells [76]. It was shown on neuroblastoma xenografts in a CD1-nu mouse model that a ketogenic diet consisting of fat (25% medium-chain triglycerides and 75% long-chain triglycerides) and carbohydrates + protein gave the same effective therapeutic effect against neuroblastoma as did the classical ketogenic diet combined with caloric restriction [77].…”

Ketogenic diets as an adjuvant therapy for glioblastoma (KEATING): a randomized, mixed methods, feasibility study

“…KD is an 'umbrella term' used to describe high fat, low carbohydrate, adequate protein diets which promote the utilization of fat for energy, in the form of ketones. Initially hypothesized to work by exploiting the 'Warburg effect' [6][7][8][9], newer theories have proposed other mechanisms of action, with ketone bodies and medium chain triglyceride (MCT) fats playing a role in tumor metabolism, rather than or in addition to a reduction in glucose [10][11][12][13]. Animal models of glioma have shown that KD potentiates the effects of radiotherapy [14], reduce peri-tumoral edema [15] and reduce tumor angiogenesis [7].…”

Impact of extracellular matrix properties on neuroblastoma genomic heterogeneity

“…We sequenced a small customized panel (NB-mechanopanel) of speci c genes, with mutations previously described in NB related to cytoskeleton remodeling and extracellular matrix changes, and other genes related to NB and cancer in general (Table S2). In SK-N-BE(2) cell line and in all samples derived from it, we identi ed two mutations described as p.C135F in TP53 [45] and p.N755K in ATRX [46], de ned as pathogenic in the COSMIC database. The p.I1590 = and p.P1323L variants of COL11A1 (in 1p), and the intronic polymorphisms c.1680-9045C > G and c.54-20738C > T of DOCK8 (in 9p) were not detected in the majority of VN-KO tumors that had heterozigotic deletions of both chromosomal regions (1p-and 9p-), despite their presence in the rest of the samples, including in the 2D cultured cell line, with allelic frequency of approximately 0.4.…”