Press-pulse: a novel therapeutic strategy for the metabolic management of cancer 癌症代謝管理的新治療策略

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Several byproducts of amino acid fermentation can also accumulate in the tumor microenvironment including acetate, glutamate, alanine, succinate, and ammonia. Although acetate has been considered a potential fuel for supporting tumor cell growth [117, 118], acetate levels are generally low in the circulation [119]. Jaworski et al. recently provided a comprehensive discussion on the potential role of acetate in tumor metabolism [120]. It should be recognized that with the exception of glucose and glutamine, none of the other potential fuels needed for tumor cell fermentation would likely be available in sufficient quantities to drive robust tumor cell growth. As many amino acids are synthesized from glucose and glutamine, targeting glucose and glutamine will deprive the microenvironment of fermentable fuels. Hence, the restriction of glucose and glutamine becomes of prime importance for targeting tumor cell growth and survival. The role of glucose and glutamine in driving tumor cells energy metabolism is shown in Fig. 1.

Fig. 1

Targeting Glucose and Glutamine for the Metabolic Management of Cancer. Cancer cells are largely dependent on glucose and glutamine for survival and growth. Energy through fermentation metabolism (substrate level phosphorylations, SLP) in glycolysis and the tricarboxylic acid cycle (TCA) will compensate for reduced energy through oxidative phosphorylation (OxPhos) that occurs in tumor cells. The yellow ovals indicate the three source of cellular ATP production. Glucose carbons can be used for both the glycolytic and pentose phosphate (PPP) pathways to supply ATP and precursors for lipid and nucleotide synthesis, as well as for glutathione production. Glutamine provides its amide nitrogen for ammonia and nucleotide synthesis. The glutamine-derived glutamate provides anapleurotic carbons to the TCA cycle through α-KG for protein synthesis while also providing ATP through TCA cycle SLP. TCA cycle substrate level phosphorylation through the succinate thiokinase reaction can generate significant cellular ATP under hypoxia especially in tumor cells with defective respiration [78]. The glutamine-derived glutamate is also used for glutathione production that protects tumor cells from oxidative stress. Glucose and glutamine targeting will thus make cancer cells vulnerable to oxidative stress therapies. The simultaneous targeting of glucose and glutamine through the press-pulse therapeutic strategy will starve tumor cells of energy production while blocking their ability to synthesize proteins, lipids, and nucleotides. Glucose and glutamine can also be generated internally through the lysosomal digestion of phagocytosed glycoconjugates and proteins (see text). An elevation of non-fermentable ketone bodies through, calorie restriction, ketogenic diets, or supplementation will provide normal cells with an alternative energy source to glucose while also protecting them from oxidative stress. Ghost mitochondria are those containing little or no inner mitochondrial membranes (cristae), which are essential for normal OxPhos function [67, 282, 283]

Tumor cell energy metabolites from cannibalism and phagocytosis

Emerging evidence indicates that macrophages, or their fusion hybridization with neoplastic stem cells, are the origin of metastatic cancer cells [5, 89, 121, 122, 123, 124]. Radiation therapy can enhance fusion hybridization that could increase risk for invasive and metastatic tumor cells [91,125]. Cannibalism and phagocytosis of cellular debris are well known characteristics of macrophages and of myeloid cancer cells with macrophage properties [121, 126, 127, 128, 129, 130,131]. Shelton showed that glioblastoma cells with myeloid properties could survive in Matrigel (extracellular matrix material) in the absence of added glucose and glutamine [132]. The gradual accumulation of lactate in the media suggested that the glioblastoma cells survived through lysosomal digestion and aerobic fermentation of glycoconjugates present in the Matrigel. Glioblastoma cell death occurred immediately following the addition of chloroquine, which neutralizes lysosomal acidity and digestion [132]. Shelton’s findings are consistent with the more recent findings of Kamphorst et al. in showing that pancreatic ductal adenocarcinoma cells could obtain glutamine under nutrient poor conditions through lysosomal digestion of extracellular proteins [133]. It will therefore become necessary to also target lysosomal digestion, under reduced glucose and glutamine conditions, to effectively manage those invasive and metastatic cancers that express cannibalism and phagocytosis.

Genome integrity and energy metabolism

Emerging evidence indicates that the function of DNA repair enzymes and the integrity of the nuclear genome are dependent to a large extent on the energy derived from normal respiration [134, 135, 136, 137, 138, 139, 140, 141, 142]. Previous studies in yeast and mammalian cells show that disruption of aerobic respiration can cause mutations (loss of heterozygosity, chromosome instability, and epigenetic modifications etc.) in the nuclear genome [28, 141, 143, 144]. A protracted reliance on fermentation causes oxidative stress leading to the production of reactive oxygen species (ROS) mostly through the mitochondrial coenzyme Q couple [145]. In addition to their role in oncogenic signaling, excess ROS production damages mitochondrial function, and can be both carcinogenic and mutagenic [146, 147]. The somatic mutations and genomic instability seen in tumor cells thus arise from a protracted reliance on fermentation energy metabolism and a disruption of redox balance through excess oxidative stress.

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