Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma

Abstract

Glioblastoma (GBM) is an aggressive primary human brain tumour that has resisted effective therapy for decades. Although glucose and glutamine are the major fuels that drive GBM growth and invasion, few studies have targeted these fuels for therapeutic management. The glutamine antagonist, 6-diazo-5-oxo-L-norleucine (DON), was administered together with a calorically restricted ketogenic diet (KD-R) to treat late-stage orthotopic growth in two syngeneic GBM mouse models: VM-M3 and CT-2A. DON targets glutaminolysis, while the KD-R reduces glucose and, simultaneously, elevates neuroprotective and non-fermentable ketone bodies. The diet/drug therapeutic strategy killed tumour cells while reversing disease symptoms, and improving overall mouse survival. The therapeutic strategy also reduces edema, hemorrhage, and inflammation. Moreover, the KD-R diet facilitated DON delivery to the brain and allowed a lower dosage to achieve therapeutic effect. The findings support the importance of glucose and glutamine in driving GBM growth and provide a therapeutic strategy for non-toxic metabolic management.

Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer

“…We recently proposed that most of the ATP synthesized in tumor cells would come from mitochondrial substrate level phosphorylation (mSLP) at the succinate ligase reaction (46). Evidence showing that mSLP can compensate for OxPhos deficiency in cancer is emerging (57)(58)(59)(60). mSLP could also compensate for minimal energy production through glycolysis due to the predominance of the glycolytic pyruvate kinase M2 (PKM2) isoform, which produces less ATP than the PKM1 isoform (61).…”

“…Macrophages (seeds) are known to infiltrate organs (soil) nonrandomly (109). As glutamine is a major fuel for macrophages (130,131), targeting the availability of glutamine together with glucose becomes a rational, yet largely overlooked, therapeutic strategy for managing metastatic cancer (60).…”

“…Ketogenic diet appears to work better when used with glutamine targeting and is consumed in restricted amounts (60). The simultaneous targeting of glycolysis and glutaminolysis is now emerging as a potential therapeutic strategy for managing a broad range of cancers including breast cancer (60,179,180). KMT reduces circulating levels of glucose and insulin that are needed for rapid tumor growth (176).…”

“…By reducing blood glucose, KMT would also reduce the immunosuppressive effects of lactic acid in the tumor microenvironment (202). Recent studies show that therapeutic ketosis can facilitate drug delivery through the blood-brain barrier (60,203). This would be important in helping to target breast cancer cells that metastasize to the brain.…”

“…The glutamine dehydrogenase inhibitor, epigallocatechin gallate (EGCG) is also proposed to target glutamine metabolism through an effect on glutamate dehydrogenase (207). The glutaminase inhibitor, 6-diazo-5oxo-L-norleucine (DON), is a powerful glutamine-targeting drug that can work synergistically with a restricted KD for managing brain cancer and metastasis (60,208,209). Hence, KMT can, (a), target the multiple drivers of rapid tumor growth, (b), facilitate drug delivery to the tumor tissue, (c), work synergistically with glutamine-targeting drugs, and, (d), enhance the metabolic efficiency in normal healthy cells.…”