If cancer is primarily a disease of energy metabolism as reviewed here, then rational approaches to cancer management can be found in therapies that specifically target energy metabolism. Although mitochondrial replacement therapy could in principle restore a more normal energy metabolism and differentiated state to tumor cells, it is unlikely that this therapeutic approach would be available in the foreseeable future. However, numerous studies show that dietary energy restriction is a general metabolic therapy that naturally lowers circulating glucose levels and significantly reduces growth and progression of numerous tumor types to include cancers of the mammary, brain, colon, pancreas, lung, and prostate [
10,
247‐
256]. The influence of energy restriction on tumor growth, however, can depend on host background and tumor growth site, as energy restriction is effective in reducing the U87 human glioma when grown orthotopically in the brain of immunodeficient SCID mice [
175], but not when grown outside the brain in non-obese diabetic SCID mice [
257]. Nevertheless, the bulk of evidence indicates that dietary energy restriction can retard the growth rate of many tumors regardless of the specific genetic defects expressed within the tumor.
Targeting Glucose
Reduced glucose availability will target aerobic glycolysis and the pentose phosphate shunt; pathways required for the survival and proliferation of many types of tumor cells. Dietary energy restriction specifically targets the IGF-1/PI3K/Akt/HIF-1α signaling pathway, which underlies several cancer hallmarks to include cell proliferation, evasion of apoptosis, and angiogenesis [
168,
175,
176,
250,
251,
254,
258‐
265]. Calorie restriction also causes a simultaneous down-regulation of multiple genes and metabolic pathways regulating glycolysis [
266‐
268]. This is important, as enhanced glycolysis is required for the rapid growth and survival of many tumor cells [
21,
22]. In addition, recent findings suggest that a large subset of gliomas have acquired mutations in the TCA cycle gene, isocitrate dehydrogenase (
IDH1) [
105]. Such mutations are expected to limit the function of the TCA cycle, thus increasing the glycolytic dependence of these tumors. Tumors with these types of mutations could be especially vulnerable to management through dietary energy restriction. Hence, dietary energy or calorie restriction can be considered a broad-spectrum, non-toxic metabolic therapy that inhibits multiple signaling pathways required for progression of malignant tumors regardless of tissue origin.
Besides lowering circulating glucose levels, dietary energy restriction elevates circulating levels of fatty acids and ketone bodies (β-hydroxybutyrate and acetoacetate) [
266,
269,
270]. Fats and especially ketone bodies can replace glucose as a primary metabolic fuel under calorie restriction. This is a conserved physiological adaptation that evolved to spare protein during periods of starvation [
271,
272]. Many tumors, however, have abnormalities in the genes and enzymes needed to metabolize ketone bodies for energy [
273‐
275]. A transition from carbohydrate to ketones for energy is a simple way to target energy metabolism in glycolysis-dependent tumor cells while enhancing the metabolic efficiency of normal cells [
276,
277]. The shift from the metabolism of glucose to the metabolism of ketone bodies for energy is due largely to the shift in circulating levels of insulin and glucagon, key hormones that mediate energy metabolism. Insulin, which stimulates glycolysis, is reduced under dietary restriction, while glucagon, which inhibits glycolysis and mobilizes fats, is increased. Glucose reduction not only reduces insulin, but also reduces circulating levels of IGF-1, which is necessary for driving tumor cell metabolism and growth [
168,
278]. Glucocorticoids, which enhance glucagon action and the stress response, are also elevated under dietary energy restriction [
261]. The shift in levels of these metabolic hormones would place greater physiological stress on the tumor cells than on normal cells since the tumor cells lack metabolic flexibility due to accumulated genetic mutations [
10,
15,
277].
Inferences that tumor cells have a growth advantage over normal cells are inconsistent with principles of evolutionary biology [
10,
277]. Although viewed as a growth advantage, the dysregulated growth of tumor cells is actually an aberrant phenotype. How can tumor cells that express multiple mutations and mitochondrial abnormalities be more "fit" or "advantaged" than normal cells that possess a flexible genome, normal respiratory capacity, and adaptive versatility? The short answer is that they are not. Normal cells can grow much faster than tumor cells during normal wound repair. Metabolism of ketone bodies and fatty acids for energy requires inner mitochondrial membrane integrity and efficient respiration, which tumor cells largely lack [
10,
273,
278]. In contrast to the tumor cells, normal cells evolved to survive extreme shifts in the physiological environment and can readily adapt to fat metabolism when glucose becomes limiting. Glucose transporter expression is higher in mouse brain tumor cells than in neighboring normal cells when circulating glucose levels are high, but the transporter phenotype of these cells becomes reversed under dietary energy restriction [
168]. These findings highlight the different responses to energy stress between the metabolically incompetent tumor cells and competent normal cells. Consequently, a shift in energy metabolism from glucose to ketone bodies protects respiratory competent normal cells while targeting the genetically defective and respiratory challenged tumor cells, which depend more heavily on glycolysis than normal cells for survival [
10,
278,
279].
Proof of concept for cancer metabolic therapy was illustrated for the management of malignant astrocytoma in mice, and malignant glioma in children [
273,
276,
280]. Prostate and gastric cancer also appears manageable using low carbohydrate ketogenic diets [
252,
281,
282]. Recent studies show that dietary energy restriction enhances phosphorylation of adenosine monophosphate kinase (AMPK), which induces apoptosis in glycolytic-dependent astrocytoma cells, but protects normal brain cells from death [
283]. This further illustrates the differential response of normal cells and tumor cells to energy stress.
A possible concern is how any therapy, which reduces food intake and body weight, can be recommended to individuals who might be losing body weight because of cancer cachexia. Cancer cachexia generally involves anorexia, weight loss, muscle atrophy, and anemia [
284,
285]. Although some cancer patients could be obese, rapid weight loss from cachexia involving both proteins and fat is a health concern [
285]. It is important to recognize that pro-cachexia molecules such as proteolysis-inducing factor are released from the tumor cells into the circulation and contribute to the cachexia phenotype [
286,
287]. By targeting the glycolytically active tumor cells that produce pro-cachexia molecules, restricted diet therapies can potentially reduce tumor cachexia [
278,
287]. These therapies could be supplemented with omega-3 fatty acids, which can also reduce the cachexia phenotype [
285]. Omega-3 fatty acids from fish oil also have the benefit of maintaining low glucose while elevating ketone levels. Once the tumor becomes managed, individuals can increase caloric consumption to achieve weight gain.
Metabolic therapies involving calorie restriction should be effective in targeting energy-defective cells within a given tumor, and for managing a broad range of glycolysis-dependent tumors. There are no known drugs that can simultaneously target as many tumor-associated signaling pathways as can calorie restriction [
168]. Hence, energy restriction can be a cost-effective adjuvant therapy to traditional chemo- or radiation therapies, which are more toxic, costly, and generally less focused in their therapeutic action, than is dietary energy restriction.
In addition to dietary energy restriction, several small molecules that target aerobic glycolysis are under consideration as novel tumor therapeutics to include 2-deoxyglucose, lonidamine, 3-bromopyruvate, imatinib, oxythiamine, and 6-aminonicotinimide among others [
129,
288‐
290]. Toxicity can become an issue, however, as some of these compounds target pathways other than glycolysis or nucleotide synthesis and high dosages are sometimes required to achieve efficacy
in vivo. A recent study found significant therapeutic synergy in combining low doses of 2-deoxyglucose with a calorie restricted ketogenic diet for managing malignant astrocytoma in mice [
291].
It appears that the therapeutic efficacy of anti-glycolytic cancer drugs could be significantly enhanced when combined with dietary energy restriction. The administration of anti-glycolytic drugs together with energy restricted diets, which lower circulating glucose levels while elevating ketone levels, could act as a powerful double "metabolic punch" for the rapid killing of glycolysis dependent tumor cells. This therapeutic approach could open new avenues in cancer drug development, as many drugs that might have minimal therapeutic efficacy or high toxicity when administered alone could become therapeutically relevant and less toxic when combined with energy restricted diets.
Targeting Glutamine
Although dietary energy restriction and anti-glycolytic cancer drugs will have therapeutic efficacy against many tumors that depend largely on glycolysis and glucose for growth, these therapeutic approaches could be less effective against those tumor cells that depend more heavily on glutamine than on glucose for energy [
47,
65‐
67]. Glutamine is a major energy metabolite for many tumor cells and especially for cells of hematopoietic or myeloid lineage [
47,
49,
294,
295]. This is important as cells of myeloid lineage are considered the origin of many metastatic cancers [
17,
190,
204,
221,
230]. Moreover, glutamine is necessary for the synthesis of those cytokines involved in cancer cachexia including tumor necrosis factor alpha, (TNF-α) and the interleukins 1 and 6 (IL-1 and -6) [
66,
284,
295,
296]. This further indicates a metabolic linkage between metastatic cancer and myeloid cells, e.g., macrophages. It therefore becomes important to also consider glutamine targeting for the metabolic management of metastatic cancer.
Glutamine can be deaminated to glutamate and then metabolized to α-ketoglutarate, a key metabolite of the TCA cycle [
49,
67]. This occurs either through transamination or through enhanced glutamate dehydrogenase activity depending on the availability of glucose [
67]. Besides generating energy through substrate level phosphorylation in the TCA cycle, i.e., transphosphorylation of GTP to ATP, the anapleurotic effect of glutamine can also elevate levels of metabolic substrates, which stimulate glycolysis [
49,
66]. Glutamine metabolism can be targeted in humans using the glutamine binding drug, phenylacetate, or the glutamine analogue DON (6-Diazo-5-oxo-L-norleucine) [
297]. Toxicity, however, can be an issue in attempts to target glutamine metabolism using DON [
130,
294]. Recent studies suggest that the green tea polyphenol (EGCG) could target glutamine metabolism by inhibiting glutamate dehydrogenase activity under low glucose conditions [
67]. This and other glutamine-targeting strategies could be even more effective when combined with energy restricting diets, which lower glucose levels while elevating ketone bodies. Hence, effective non-toxic targeting of both glucose and glutamine metabolism should be a simple therapeutic approach for the global management of most localized and metastatic cancers.