Dialysis as a Novel Adjuvant Treatment for Malignant Cancers

Abstract

Cancer metabolism is characterized by an increased utilization of fermentable fuels, such as glucose and glutamine, which support cancer cell survival by increasing resistance to both oxidative stress and the inherent immune system in humans. Dialysis has the power to shift the patient from a state dependent on glucose and glutamine to a ketogenic condition (KC) combined with low glutamine levels-thereby forcing ATP production through the Krebs cycle. By the force of dialysis, the cancer cells will be deprived of their preferred fermentable fuels, disrupting major metabolic pathways important for the ability of the cancer cells to survive. Dialysis has the potential to reduce glucose levels below physiological levels, concurrently increase blood ketone body levels and reduce glutamine levels, which may further reinforce the impact of the KC. Importantly, ketones also induce epigenetic changes imposed by histone deacetylates (HDAC) activity (Class I and Class IIa) known to play an important role in cancer metabolism. Thus, dialysis could be an impactful and safe adjuvant treatment, sensitizing cancer cells to traditional cancer treatments (TCTs), potentially making these significantly more efficient.

Keywords: HDAC; cancer; chemotherapies; dialysis; immunotherapies; ketone bodies; radiotherapies; redox balance.

Figure 1

Graphs outlining the possible differences between the metabolite levels achieved over time from (A) a ketogenic diet [26,28] or fast [20,29], and from (B) dialysis. A comparably short dialysis treatment would shift the patient to a ketogenic metabolic condition, where high ketone and low glutamine levels will be unfavorable for cancer cells, but not healthy cells. A short dialysis treatment shifts the patient from one metabolic condition to another, unfavorable for the cancer but not for the patient as a whole.

Figure 2

Suggested effects of CancerDialysis on the efficacy of TCT. (↑) indicates an increase and (↓) indicates a decrease.

Figure 3

(A) Hemodialysis is the choice of renal replacement therapy, typically performed with a blood access in the arm (a fistula), for most patients that needs therapy for end stage renal disease, and in 2010 more than two million patients received dialysis treatment [46]. The treatment is generally well-tolerated with minor side effects [47]. (B) A tunneled central dialysis catheter is also used for chronic patients but also for temporary access to the blood. It allows for long-term access to the vein and is bidirectional, allowing flows in and out at the same time.

Figure 4

The dialysis simulation is utilizing a standard dialysis setting of 300 mL/min in blood flow and a 500 mL/min in dialysis fluid flow; the physiological model we have used for the simulation has been presented by Todd et al. [53,54]. When diet starts, the available glycogen level is set to 100 g in the liver [49,50,55]. When dialysis starts, the blood glucose level will fall towards 3 mmol/L if a dialysis fluid glucose concentration of 2 mmol/L is used; if the dialysis fluid glucose concentration is 0 mmol/L the simulation indicates a fall toward 2 mmol/L of glucose in the blood.

Figure 5

During CancerDialysis healthy cells as well as cancer cells (except hepatic and red blood cells) must shift from their dependency on glucose and amino acids towards ketones. This shift from a normal physiological state to a ketogenic condition, is a shift that healthy cells are programmed to do timely during food shortages, an ability that cancer cells, which are more addicted to fermentable fuels as glucose and glutamine, may be more vulnerable to. To induce KC and low glutamine levels with dialysis may therefore work as a multi-combinatorial treatment, potentially with few side effects when healthy cells timely can adapt to KC.

Figure 6

Schematic view over most important NADPH-related pathways in the cytosol and the major pathway for lactate and hydrogen ion production. NADPH plays a vital role in the reduction of the increased oxidative stress in cancer [23,76,77,78]. NADPH is known to be produced through several fermentable metabolic pathways, where most depend on glucose or glutamine [78,79]. ➀ The most important pathway for NADPH production is the pentose phosphate pathway (PPP) that emanates from glycolysis and depends on glucose for its function [78,79,80]. ➁ The second most important pathway for NAPDH production is conversion from malate to pyruvate, fueled by glutamine and increasingly important during glucose deprivation [62,79,80,81]. ➂ In some cancers there is another pathway for NADPH production, mainly glutamine fueled, utilizing isocitrate dehydrogenase [77,79,80]. ➃ Hydrogen ions are produced as a product of the glycolysis pathway (red) and are exported out from the cytosol, thereby contributing to the low pH in the TME [37,69]. ➄ Lactate can be produced either both from glucose (red) or from glutamine (blue) and is exported out from the cytosol (black) and contributes to high lactate levels in TME [37,69]. ➅ Schematically describing the NADPH pool in the cytosol and how it is constantly refilled from pathways mainly dependent on glucose and glutamine [11,79,81]. ➆ The reduction power from NADPH is used to detoxify the cells from oxidative stress. Glutathione (GSH) is one of the most important scavengers of reactive oxygen species (ROS) in cancer cells and when oxidized by ROS to glutathione disulfide (GSSG) it is reduced back to GSG by NADPH [11,74].

Figure 7

When ketone levels increase in the blood, the gluconeogenesis in the liver is reduced [85,86]. Ketolysis can occur in almost all healthy cells [39,82]. Ketones enter Krebs cycle through acetyl-CoA requiring oxaloacetate to enter [39,82]. Comparably, ketolysis is a short and straight pathway, and do not contribute to the production of anti-oxidative power or metabolites in cancer cells as glycolysis or glutaminolysis do (compare Figure 6).

Figure 8

It is well known that the TME is a harsh environment for the infiltrating leukocytes. CD8 T cells and natural killer cells are important immune cells for targeting cancer cells and are known to be inactive at low pH and high lactate levels [15,37,70,104,105,106,107,108].

Figure 9

Elevated HDACs are linked to oncogenesis and HDACs have pleiotropic effects and promote many oncogenes. Reducing HDACs through HDAC inhibitors can improve therapeutic efficacy of TCTs. For example, the strong suppression of apoptosis seen in many cancer cells will be reduced through the inhibition effects that KBs are shown to induce at physiological levels [6,40,120,121,128,129].