As described by Warburg more than 50 years ago, tumor cells maintain a high glycolytic rate even in conditions of adequate oxygen supply. However, most of tumors are subjected to hypoxic conditions due to the abnormal vasculature that supply them with oxygen and nutrients. Thus, glycolysis is essential for tumor survival and spread. A key step in controlling glycolytic rate is the conversion of fructose-6-P to fructose-1,6-P(2) by 6-phosphofructo-1-kinase (PFK-1). The activity of PFK-1 is allosterically controlled by fructose-2,6-P(2), the product of the enzymatic activity of a dual kinase/phosphatase family of enzymes (PFKFB1-4) that are increased in a significant number of tumor types. In turn, these enzymes are induced by hypoxia through the activation of the HIF-1 complex (hypoxia-inducible complex-1), a transcriptional activator that controls the expression of most of hypoxia-regulated genes. HIF-1 complex is over expressed in a variety of tumors and its expression appears to correlate with poor prognosis and responses to chemo or radiotherapy. Thus, targeting PFKFB enzymes, either directly or through inhibition of HIF-1, appears as a promising approach for the treatment of certain tumors.
Energy Boost: The Warburg Effect Returns in a New Theory of Cancer — Garber 9
Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports
Nebeling LC, Miraldi F, Shurin SB, Lerner E.
Nutrition Department, Case Western Reserve University, School of Medicine, Cleveland, Ohio, USA.
OBJECTIVE: Establish dietary-induced ketosis in pediatric oncology patients to determine if a ketogenic state would decrease glucose availability to certain tumors, thereby potentially impairing tumor metabolism without adversely affecting the patient’s overall nutritional status. DESIGN: Case report. SETTING: University Hospitals of Cleveland. SUBJECTS: Two female pediatric patients with advanced stage malignant Astrocytoma tumors. INTERVENTIONS: Patients were followed as outpatients for 8 weeks. Ketosis was maintained by consuming a 60% medium chain triglyceride oil-based diet. MAIN OUTCOME MEASURES: Tumor glucose metabolism was assessed by Positron Emission Tomography (PET), comparing [Fluorine-18] 2-deoxy-2-fluoro-D-glucose (FDG) uptake at the tumor site before and following the trial period. RESULTS: Within 7 days of initiating the ketogenic diet, blood glucose levels declined to low-normal levels and blood ketones were elevated twenty to thirty fold. Results of PET scans indicated a 21.8% average decrease in glucose uptake at the tumor site in both subjects. One patient exhibited significant clinical improvements in mood and new skill development during the study. She continued the ketogenic diet for an additional twelve months, remaining free of disease progression. CONCLUSION: While this diet does not replace conventional antineoplastic treatments, these preliminary results suggest a potential for clinical application, which merits further research.