Ketogenic Diet in the Treatment of Gliomas and Glioblastomas

Abstract

In recent years, scientific interest in the use of the ketogenic diet (KD) as a complementary approach to the standard cancer therapy has grown, in particular against those of the central nervous system (CNS). In metabolic terms, there are the following differences between healthy and neoplastic cells: neoplastic cells divert their metabolism to anaerobic glycolysis (Warburg effect), they alter the normal mitochondrial functioning, and they use mainly certain amino acids for their own metabolic needs, to gain an advantage over healthy cells and to lead to a pro-oncogenetic effect. Several works in literature speculate which are the molecular targets of KD used against cancer. The following different mechanisms of action will be explored in this review: metabolic, inflammatory, oncogenic and oncosuppressive, ROS, and epigenetic modulation. Preclinical and clinical studies on the use of KD in CNS tumors have also increased in recent years. An interesting hypothesis emerged from the studies about the possible use of a ketogenic diet as a combination therapy along with chemotherapy (CT) and radiotherapy (RT) for the treatment of cancer. Currently, however, clinical data are still very limited but encouraging, so we need further studies to definitively validate or disprove the role of KD in fighting against cancer.

The addition of arginine deiminase potentiates Mithramycin A-induced cell death in patient-derived glioblastoma cells via ATF4 and cytochrome C

“…Since AHR and cMyc cooperate in the regulation of cellular metabolism [ 53 ], the downregulation of both genes in combination explains our findings of a boosted cytotoxic effect best. Indeed, targeting the metabolism of GBM cells is promising [ 54 , 55 ].…”

Targeting fatty acid oxidation via Acyl-CoA binding protein hinders glioblastoma invasion

“…However, the assumption that GBM cells rely exclusively on carbohydrates and not on fatty acids and/or ketone bodies as a source of energy has been challenged in the last years by several groups including ours [ 10 , 11 , 13 , 56 , 57 ]. Preclinical studies interrogated the efficacy of ketogenic diets for glioma patients with contrasting results [ 58 ]. A beneficial effect was observed in a few cases [ 59 ], but also ketogenic diet was shown to boost GBM growth in other reports [ 57 ].…”

Ketogenic diet in cancer management

“…Thus, higher production of both intracellular lactate and extracellular ketone bodies can lead to the accumulation of lactate in tumor cells as a result of the competitive activity of MCTs [31]. This imbalance reduces cell growth and proliferation [28 ▪ ,31]. Also, KD targeted the glycolytic pathway by the suppression of M2 isoform of pyruvate kinase, which disrupts the process of energy production and stimulates apoptosis [29 ▪▪ ].…”

“…Besides, when glucose levels are low, the normal cells will switch to utilizing ketone bodies (ketosis) to get energy, whereas cancer cells lack this option due to having dysfunctional mitochondria [27]. In this context, the ketogenic diet affects cancer cells through two aspects: extracellular and intracellular [28 ▪ ]. Extracellularly, KD causes a reduction in glucose levels and consequently decreases insulin and IGF-1 production as well as blocking the mTOR pathway [29 ▪▪ ].…”