The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer

2007
Weihua Zhou, Purna Mukherjee, Michael A Kiebish, William T Markis, John G Mantis, and Thomas N Seyfried

Abstract

Background

Malignant brain cancer persists as a major disease of morbidity and mortality in adults and is the second leading cause of cancer death in children. Many current therapies for malignant brain tumors fail to provide long-term management because they ineffectively target tumor cells while negatively impacting the health and vitality of normal brain cells.

In contrast to brain tumor cells, which lack metabolic flexibility and are largely dependent on glucose for growth and survival, normal brain cells can metabolize both glucose and ketone bodies for energy. This study evaluated the efficacy of KetoCal®, a new nutritionally balanced high fat/low carbohydrate ketogenic diet for children with epilepsy, on the growth and vascularity of a malignant mouse astrocytoma (CT-2A) and a human malignant glioma (U87-MG).

Discussion

We found that KetoCal®, a nutritionally balanced and commercially available ketogenic diet for children with epilepsy, significantly reduced the orthotopic growth and the vascularity of the mouse astrocytoma (CT-2A) and the human glioma (U87). Moreover, KetoCal® significantly prolonged survival in the tumor-bearing mice. It is important to mention that the anti-angiogenic and growth inhibitory effects of KetoCal® were observed only when the diet was administered in restricted amounts but were not seen when the diet was administered ad libitum, or in unrestricted amounts.

These findings support previous observations that restriction of dietary calories has powerful anti-angiogenic and anti-inflammatory effects against cancer, including brain cancer [9-11,51,57,58]. Reduced caloric content lowers circulating glucose levels as we found in this study and in our previous studies [10,11]. Indeed, tumor growth is more strongly correlated with circulating glucose levels than with circulating ketone body levels [8].

The reduction in glucose levels following restriction of dietary calories largely accounts for why tumors grow minimally on either restricted ketogenic diets or on restricted high carbohydrate standard diets. Restriction of calories in humans may be difficult to achieve, however, due to issues of compliance.

Compliance may be better with KetoCal® as this diet was designed for managing refractory human epilepsy under calorically restricted conditions. CR, however, is not directly comparable in mice and humans. For example, a 40% CR diet in mice is comparable to therapeutic fasting in humans, which can be difficult for many people [30].

In addition to reducing circulating glucose levels, a restriction of total calories also reduces potential adverse effects of the high fat content of the diet since energy homeostasis is maximized under CR regardless of caloric origin [8,30]. The restricted KetoCal® diet should therefore be easier to implement than therapeutic fasting for brain cancer patients.

Although we previously showed that CR of a high carbohydrate standard diet or of a rodent ketogenic diet similarly reduce blood glucose levels, which tumor cells depend upon for survival [10,11], our findings in this study showed that administration of KetoCal® under restricted conditions was more effective in elevating circulating ketone bodies than was administration under unrestricted conditions. This is important since mild ketosis, under conditions of reduced glucose availability, is essential for enhancing the bioenergetic potential of normal brain cells [5,17,18]. Additionally, ketone bodies may directly protect normal neurons and glia from damage associated with aggressive tumor growth through a variety of neuroprotective mechanisms [59-64]. In contrast to most conventional brain tumor therapies, which indiscriminately target both normal cells and tumor cells, CR and particularly restricted ketogenic diets such as KetoCal® are the only known therapies that can target brain tumor cells while enhancing the health and vitality of normal brain cells [5,29]. In this regard, the calorically restricted ketogenic diet for brain cancer management stands apart from all conventional therapeutic approaches.

Previous studies indicate that many tumors including brain tumors are largely unable to metabolize ketone bodies for energy due to various deficiencies in one or both of the key mitochondrial enzymes, β-OHBDH and SCOT [19,21,65-68]. Our gene expression results in the mouse CT-2A and the human U87 brain tumors are consistent with these previous findings in other tumors and also support the mitochondrial defect theory of cancer [5,23,24,69]. The deficiencies in these enzymes, however, are important for tumor management only under calorically restricted conditions when glucose levels are reduced and when cells would require ketone bodies for energy. This is most evident from the analysis of tumor growth in the unrestricted KetoCal® groups where growth was rapid despite mild ketosis. This is attributed to the maintenance of high glucose levels, which the tumor cells will use for energy in preference to ketone bodies due to their dependency on glycolysis. However, when glucose becomes limited, as occurs under CR, the SCOT and β-OHBDH deficiencies would prevent tumor cells from using ketones as an alternative fuel thus metabolically isolating the tumor cells from the normal cells. We suggest that the genes for these enzymes could be useful markers for screening brain tumors and other tumor types that may be responsive to therapy using restricted KetoCal® or other restricted ketogenic diets. Further studies will be necessary to test this interesting possibility.

Long-term management of malignant brain cancer has been difficult in both children and adults. This has been due in large part to the unique anatomical and metabolic environment of the brain that prevents the large-scale resection of tumor tissue and impedes the delivery of chemotherapeutic drugs.

Conclusion

The results indicate that KetoCal® administered in restricted amounts has anti-tumor and anti-angiogenic effects in experimental mouse and human brain tumors. Furthermore, genes for ketone body metabolism will be useful for screening brain tumors that could be targeted with KetoCal® or other calorically restricted high fat low carbohydrate diets. This preclinical study in mice indicates that the restricted KetoCal® diet should be an effective alternative therapeutic option for managing malignant brain cancer in humans.