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Oncotarget, 08 Aug , 8 39 : DOI: 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. 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. Favorable and unfavorable prognoses of NB are classified on the basis of the heterogeneity of genetic changes, histologic features, and patient age [ 2 ]. Owing to intense research efforts in NB therapy, including the application of multimodal therapeutic strategies, the survival rate has markedly improved in patients with low- and intermediate-stage NB [ 3 ].
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