Review: Ketogenic diet in the treatment of cancer – Where do we stand? 評論：生酮飲食治療癌症-我們的立場是什麼？

4. Potential mechanisms of the ketogenic diet in tumorigenesis

Antitumor effects of the ketone bodies AcAc and BHB have been demonstrated in several cancer cell lines in vitro [59], [92]. However, whether the antitumor properties of KDs are exclusively attributable to the antiproliferative effects of ketone bodies and low blood glucose levels seems rather unlikely. In the following sections, we describe potential mechanisms of action of KDs in tumorigenesis.

4.1. Ketogenic diet targets glucose metabolism of cancer cells

Most solid cancers share metabolic features such as increased glucose uptake and reliance on glycolysis. In the Warburg effect, cancer cells predominantly use glycolysis for energy production accompanied by the production of lactate, paradoxically even if sufficient oxygen for respiration is present [93]. Therefore, it could be hypothesized that the Warburg effect in cancer cells could be at least partially targeted by creating chronic metabolic stress due to low glucose supply provoked by dietary intervention with a KD and/or calorie restriction.

Numerous preclinical studies on different types of cancer demonstrate that the KD, particularly in combination with calorie restriction, reduces circulating blood glucose levels (Table 1). The reduction in glucose levels is accompanied by a reduction of insulin and/or IGF levels in the blood [56], [94], [95], [96], [97], [98]. The activation of insulin and/or IGF receptor signaling pathways contributes to tumorigenesis [99]. In this context, a study including 9778 patients identified hyperinsulinemia as a risk factor in cancer prognosis [100]. Clinical studies have demonstrated a reverse correlation between the level of ketosis and the levels of glucose, insulin and/or IGF-1 [81], [85], [101].

The insulin-activated enzyme PI3K frequently exhibits enhanced activity in different types of cancer, due to PI3K gene mutations. Thus, PI3K inhibitors are considered as potent anticancer drugs. However, clinical trials have shown that targeted PI3K drugs often cause hyperglycemia [102], leading to increased insulin levels and reactivation of the PI3K pathway, which ultimately results in treatment resistance. Recently, it was shown that the KD improved the efficacy of anti-PI3K treatment and drug resistance by limiting the acute glucose-insulin feedback induced by PI3K inhibitors, thus blocking this loop [56].

In most cancer cells, accumulation of lactic acid, the major product of aerobic glycolysis, is detected [103]. It was shown that after three days of a KD, the level of lactic acid was diminished in the tumor tissue of patients with head and neck cancer [104]. In addition, reduction of another prognostic aerobic glycolysis-related marker, transketolase-like-1, was reported in patients who strictly used the KD [91].

Taken together, reduction of blood glucose seems to be a contributing factor in the effectiveness of the KD against cancer growth. Some preclinical studies showed that ad libitum KD, which failed to reduce the blood glucose level, was not able to reduce tumor growth [50], [52], [63], [98], [105], [106], [107], [108], [109], while additional calorie restriction or increasing the KD ratio led to both significant blood glucose reduction and tumor growth suppression [50], [63], [98], [106], [109]. Interestingly, in two preclinical studies, medulloblastoma and glioma did not respond to KD therapy, even though the KD (4:1) significantly reduced blood glucose [65], [97] and insulin levels [97].