When the body is under stress, it shifts into a different, less optimal metabolic state involving an increase of lactate, stress hormones, ammonia, free fatty acids, fat synthesis, and a decrease in protective carbon dioxide. Chronic stress also enhances glycolysis, which is the process that converts glucose to pyruvate or lactate, and aerobic glycolysis is considered to be a critical element in the reprogramming of energy metabolism in malignant tumors. Exposure to chronic stress commonly leads to a decrease in immune cell numbers and function, a significant immunosuppression, as well as to altered cytokine balance, inducing the sustained production of inflammatory cytokines. The immune dysfunction induced by stress also plays a role in the sustained low-grade inflammation that is closely associated with common chronic diseases including cancer. Stress hormones themselves can stimulate the proliferation of cancer cells by activating various signaling pathways and promoting cell division. They may also regulate tumor microenvironment and consequently support de novo angiogenesis, tumor growth and aggressiveness.
When lactate is increased, it targets various proteins and signaling factors that promote growth and other features of cancer, such as HIF, NF-kappaB, the kinase cascades, cyclin D1, and heme oxygenase, as well as being involved in a cyclic promotion of inflammation.
Cancer cells rely on fatty acid uptake to not only sustain their rapid proliferative rate, but also provide an essential energy source during conditions of metabolic stress. Studies have found that high levels of serum free fatty acids are associated with cancer, suggesting that fatty acid metabolism plays a role in the cancer pathology.
Ammonia was previously thought to be only a biological waste-product, but researchers are beginning to find that it actually heightens the cancer process. High levels of ammonia lead to fewer T-cells and immunotherapy resistance. Breast cancer cells have been shown to recycle ammonia to build new amino acids, actually using it to fuel tumor growth.
Carbon Dioxide helps to protect against Lactate and Ammonia
Carbon dioxide (CO2,) also previously considered a byproduct of metabolism, is now recognized as being vital to physiology and is currently being explored as a therapeutic aid in cancer treatment. It has several important roles and protects the cells in multiple ways. It influences the efficiency of the respiratory system and aerobic metabolism, affects oxygen’s release to tissues, adjusts blood pH, and influences cardiovascular functions such as vasodilation and blood pressure. It can play a role in regulating the acidic microenvironment of the tumor by forming carbonic acid and buffering pH changes. Researchers are exploring the use of carbogen (a gas mixture comprising approximately 5% CO2 and 95% O2 to augment cancer treatments. Anticipated outcomes from clinical explorations of the effects of CO2 on cancer include increased tumor oxygenation, increased tumor cell sensitivity to treatments, modulation of the tumor microenvironment, and development of new combined treatment strategies.
By bonding to amino groups, CO2 can inhibit the glycation of proteins during oxidative stress, and can limit the formation of free radicals in the blood by inhibiting of xanthine oxidase. It can reduce inflammation caused by endotoxin/LPS and lower the formation of tumor necrosis factor, IL-8 and other promoters of inflammation. CO2 protects mitochondria, maintaining (or even increasing) their ability to respire during stress. Increasingly, carbon dioxide is being used to help with inflammation and edema by inhibiting the formation of inflammatory cytokines and prostaglandins.
Carbon dioxide is being used increasingly to prevent inflammation and edema. For example, it can be used to prevent adhesions during abdominal surgery, and to protect the lungs during mechanical ventilation. It helps to inhibit the formation of inflammatory cytokines and prostaglandins, and reduces leakiness in the intestine and residual gas in the gastrointestinal tract. Some experiments show that as it decreases the production of some inflammatory materials by macrophages, including lactate.
Several mechanisms have been suggested to explain the protective role of CO2 in vivo. The most significant appears to be stabilization of the iron-transferrin complex which prevents the involvement of iron ions in the initiation of free radical reactions. CO2 has also been found to play a major role in the antioxidant defense system.
Drugs that inhibit glycolysis have been found to be useful against cancer, though inhibiting all glycolysis has major side effects. One drug investigated for its anti-cancer effects, dichloroacetate, (DCA) has several properties that work to reverse the cancer metabolism, characterized by increased glycolytic activity and reduced mitochondrial oxidation, regardless of oxygen availability (known as the Warburg effect.) The excessive glycolysis and the resulting excess of lactate provoke a state of metabolic acidosis in tumour microenvironment. Glycolysis-derived lactate is taken up by surrounding cells to support tumour growth and inhibits apoptotic cell death mechanisms. Several enzymes involved in glycolysis regulate apoptosis, and their overexpression in cancer cells contributes to apoptosis suppression Salts of DCA selectively target cancer cells, shifting their metabolism from glycolysis to oxidative phosphorylation by inhibition of pyruvate dehydrogenase kinase (PDK), the inhibitor of pyruvate dehydrogenase (PDH). PDH activation fosters mitochondrial oxidation of pyruvate and disrupts the metabolic advantage of cancer cells. Mitochondrial DNA mutations, often occurring in tumorigenesis and resulting in respiratory chain dysfunction, make malignant cells unable to sustain cellular energy demand. And by reducing lactate production, DCA counteracts the acidosis state of the tumour microenvironment, contributing to the inhibition of tumour growth.
Specifically targeting the aerobic glycolysis of the cancer metabolism would likely be a much safer target of treatment. Cell acidification, increasing CO2 from 2.5% to 5%, has been found to inhibit glycolysis and stimulate glycogen synthesis.
Ways to counter the effects of stress:
-Lowering endotoxin (bacterial overgrowth)
-B1 (increases CO2 and reduces lactate)
-Niacinamide (reduces free fatty acids)
-Carbohydrates (reduce cortisol, adrenaline, and free fatty acids)
-Salt (reduces adrenaline)
-Optimize thyroid function
-Correct any deficiencies of vitamins D, K, B6, and biotin. (involved with carbon dioxide metabolism)