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

Press-pulse: a therapeutic strategy for the gradual elimination of cancer cells

Mark Vincent suggested how a Press-Pulse strategy could be used to target tumor cells [185]. We have now expanded this concept to show how a press-pulse therapeutic strategy can be used for the non-toxic management and possible resolution of cancer. A calorie restricted ketogenic diet or dietary energy reduction creates chronic metabolic stress in the body. This energy stress acts as a press disturbance; the effects of which would be greater in the tumor cells than in the normal cells due to their dependency on fermentation energy metabolism, mitogens, anabolic signaling (IGF-1, mTOR, etc.), elevated redox stress, and mutational load. Drugs that target availability of glucose and glutamine would act as pulse disturbances in causing an acute reduction of these tumor-dependent fuels [186]. Hyperbaric oxygen therapy can also be considered another pulse disturbance in elevating ROS to a greater degree in tumor cells than in normal cells, thus promoting cancer cell death through redox stress [40]. Normal cells readily transition to ketone body metabolism for protection against ROS damage and oxidative stress. The goal therefore is to produce a therapeutic strategy that can more effectively manage cancer than can the toxic cancer therapies currently used in most standards of care. The following examples illustrate the potential of press-pulse therapeutic strategies for cancer management.

Calorie restriction and restricted Ketogenic diets: a press disturbance

Calorie restriction, water-only fasting, and restricted ketogenic diets reduce circulating glucose and insulin levels while elevating circulating levels of ketone bodies. Ketogenic diets (KDs) are low carbohydrate-high fat diets that are widely used to reduce refractory epileptic seizures in children [187, 188]. The KD can more effectively reduce glucose and elevate blood ketone bodies than can CR alone making the KD potentially more therapeutic against tumors than CR [174, 189, 190]. The protein and fat composition of the KD differs from that of Atkins-type diets in having comparatively less protein and more fat than the Atkins diets. This is important as several amino acids found in proteins can be deaminated to form pyruvate, which can then be metabolized to form glucose through gluconeogenesis [191]. Campbell showed that tumor growth in rats is greater under high protein (>20%) than under low protein content (<10%) in the diet [192]. Protein amino acids can be metabolized to glucose through the Cori cycle. The fats in KDs used clinically also contain more medium chain triglycerides than do Atkins diets. Consequently, blood glucose levels will be lower and ketone body levels will be higher with KDs than with Atkins-type diets. Calorie restriction, fasting, and restricted KDs are anti-angiogenic, anti-inflammatory, and pro-apoptotic and thus can target and eliminate tumor cells through multiple mechanisms [114, 166, 171, 174, 182, 193, 194]. Ketogenic diets can also spare muscle protein, enhance immunity, and delay cancer cachexia, which is a major problem in managing metastatic cancer [195, 196, 197, 198].

The therapeutic effects of KDs used alone or in combination with other therapies have been documented in preclinical studies for several cancer models including neuroblastoma [199, 200], lung cancer [201], prostate cancer [202, 203], breast and ovarian cancers [204, 205], head & neck cancers [204], colon cancer [206], and pancreatic cancer [198]. These preclinical studies are also motivating case reports and pilot studies in humans with brain cancer and other cancers [169, 181,207, 208, 209, 210, 211, 212, 213, 214]. It is clear from these studies and other studies in children and adults with cancer that KDs are generally safe and well tolerated [168, 212, 213, 215, 216, 217], These observations are also consistent with decades of research obtained from evaluation of children treated with KDs for epilepsy management [218]. Information on ketogenic diets can be obtained from the Charlie Foundation web site (https://www.charliefoundation.org).

We recently developed the Glucose/Ketone Index calculator (GKIC) to assess the potential therapeutic effects of various low-carbohydrate and KDs for brain cancer management [189]. The GKIC is a simple tool that measures the ratio of blood glucose to blood ketones and can help monitor the efficacy of metabolic therapy in preclinical animal models and in clinical trials for malignant brain cancer or for any cancer that expresses aerobic fermentation. GKI values of 1.0 or below are considered therapeutic, though therapeutic benefit appears to be associated more with elevated ketone bodies and suppression of insulin than with reduced glucose [190, 215]. However, the elevation of ketone body levels is generally greater when blood glucose levels are lower than when glucose levels are higher [174, 219, 220]. The GKI can therefore serve as a biomarker to assess the therapeutic efficacy of various diets in a broad range of cancers.

Reduced glucose availability and suppression of insulin signaling will produce chronic energy stress on those tumor cells that depend primarily on glucose for growth and survival. It is important to remember that insulin drives glycolysis through stimulation of the pyruvate dehydrogenase complex [221, 222]. Reduced levels of glucose will also reduce substrates for both the glycolytic and the pentose phosphate pathways thus reducing cellular energy, and the synthesis of glutathione and nucleotide precursors (Fig. 1).

The water-soluble ketone bodies (D-β-hydroxybutyrate and acetoacetate) are produced largely in the liver from adipocyte-derived fatty acids and ketogenic dietary fat. Ketone bodies bypass glycolysis and directly enter the mitochondria for metabolism to acetyl-CoA [223]. In contrast to fatty acid metabolism, which generates both NADH and FADH₂, ketone body metabolism generates only NADH [145]. Moreover, ketone body metabolism does not induce mitochondrial uncoupling in contrast to metabolism of saturated fatty acids [145]. The metabolism of D-β-hydroxybutyrate in normal cells will therefore increase the redox span between Complexes I and III, thus increasing the delta G’ of ATP hydrolysis while, at the same time, reducing ROS formation through the Complex II coenzyme Q couple [224, 225]. Due to mitochondrial defects, tumor cells cannot exploit the therapeutic benefits of burning ketone bodies as normal cells would. Indeed, racemic mixtures of D-/L-ketone bodies can be toxic to tumor cells under both low and high glucose conditions [57, 190]. Fine et al. found that uncoupling protein 2 is overexpressed in tumor cells, but not in normal control cells [226]. This finding provides a plausible molecular mechanism by which ketone bodies spare normal cells but suppresses growth in cancer lines.