Ketogenic diets mimic the fasting state, wherein the body responds to the lack of glucose by producing ketones for energy. Excess lactate production, which is part of the Warburg effect, compensates for ATP production defects caused by dysfunctional mitochondrial oxidative phosphorylation. 2,4 The resulting tumor dependence on glucose can be exploited with KD use. Ketogenic diets selectively starve tumors by providing the fat and protein that otherwise could not be used by glucose-dependent tumor cells.
In KDs, the 4:1 ratio of high fat to low carbohydrates mimics the metabolic effects of starvation (Figure 2). These diets slow cancer by inhibiting insulin/IGF and downstream intracellular signaling pathways, such as
Ketogenic Diet Benefits
There are concerns about providing protein to patients who are at risk for renal problems. However, mouse models of diabetic nephropathy showed improved renal function with KD use. The hypothesis was that KD use, which produces prolonged elevated 3-β-hydroxybutyric acid levels, also reduces molecular responses to glucose and consequently reduces renal damage. 6 Use of the diet also reduced pain and inflammation in both juvenile and adult rats. Mechanisms of action were thought to be reduced reactive oxygen species and increased central adenosine levels. 7,8
Adverse Effects
Dieting is of concern to cancer patients worried about additional weight loss. The standard diet is made up predominantly of carbohydrates and is high in caloric value (Figure 3). Beck and Tisdale investigated the effect of KD use on delaying cachexia in mouse models of colon carcinoma. They found that dieting was more effective than insulin in reversing weight loss and had the added effect of reducing tumor size. 7 Moreover, Tisdale and colleagues found that KD use in cachectic cancer patients could promote weight gain. 8
A possible explanation is that healthy tissue nutrition selectively delays tumor growth, while cancer cells are deprived of nutrition (carbohydrates). A therapeutic weight plateau should follow initial weight loss with KD, in contrast to pathologic rapid weight loss in non-KD patients. 9 Kidney stones, gout, and symptomatic hypoglycemia were also potential expected adverse effects (AEs).
Case Reports
In 1962, the New York Department of Mental Hygiene published an article about 2 women whose metastatic cancers disappeared after a series of daily hypoglycemiainduced insulin comas (brief and reversible). These patients could not undergo conventional electric shock therapy, hence, the medically induced psychotherapy. Not only did their psychotic and depressive symptoms resolve, but their cancers (grossly visible cervical cancer and metastatic melanoma) became undetectable as early as 2 months into treatment. 10 Zuccoli and colleagues reported on a glioblastoma that was effectively treated with temozolomide oral chemotherapy after the patient was weaned off steroids. The patient had a radiographic response and good tumor control for about a year, before discontinuing the diet. She transitioned to chemotherapy, which included bevacizumab (antivascular endothelial growth factor), but the disease progressed and she died. 11 In addition, during 8 weeks of ketogenic dieting, 2 pediatric female astrocytoma patients experienced improved mood and showed decreased glucose uptake on PET-computed tomography (PET-CT) of their tumor sites. One of these patients continued the diet and remained disease-free another 12 months. 12 These early case reports provide compelling evidence for further research into the role of glucose metabolism in cancer
treatment.
