Breast Cancer.
Health Strategy.

Alternative therapy for breast cancer (#2).

Metabolic correction.

Somatic mutations of DNA genes are still considered the main factor in the occurrence of cancer. However, modification of nuclear DNA is only a part of the overall picture of the tumor process, and not its main cause. Even multiple mutations in nuclear DNA do not provide the cell with the inevitable cancerous characteristics.

Several studies have shown that when the nucleus of a cancer cell was combined with the contents of a normal cell, signs of malignancy did not appear * * * * *. Even in the presence of tumor-associated mutations, the carcinogenicity of many types of tumors was suppressed when the tumor cell nucleus was introduced into the cytoplasm of a normal cell * * * *. Conversely, carcinogenicity increased when the contents of a cancer cell were combined with the nucleus of a normal cell * *.

But this was about the fusion of material, but what if we try to cross-transplant the nuclei of normal and cancer cells? Such experiments have also been carried out. When the nucleus in a cancer cell was replaced with that of a healthy cell, it continued to show malignancy. And when in a healthy cell the nucleus was replaced by the nucleus of a cancer cell, it continued to show non-malignant * *.

The nuclei of cancer cells after their transplantation into a healthy cytoplasm formed normal tissues *. From cancer cells introduced into early embryos, healthy tissues and organs were formed *. After the introduction of the nucleus of a cancerous frog cell into an ovum with a healthy nucleus previously removed from it, the ovum developed into a healthy tadpole *. If, as it is stubbornly asserted, nuclear DNA gene mutations were indeed the only, or even the main, cause of cancer, such miracles would not be possible. The malignant characteristics would have to be carried along with the nucleus of the malignant cell.

Intrigued by these discoveries, researchers conducted similar experiments with mitochondrial transfer. When mitochondria of a normal cell were added inside a tumor cell, the oncogenic phenotype of the latter was suppressed * * *, and its sensitivity to chemotherapy was aggravated *. At the same time, when mitochondria of a tumor cell were added inside a normal cell, the oncogenic phenotype of the latter was enhanced * *. Thus, the degree of malignancy of a cell is dictated by the state of its mitochondria and, possibly, other cell organelles.

Indeed, intracellular factors can suppress the tumor phenotype * or, conversely, stimulate it. Mutations in mitochondrial DNA or other factors can disrupt the oxidative phosphorylation process *, forcing the cell to turn to glycolytic energy production. In addition, persistent pathogenic mutations in mtDNA can also lead to epigenetic changes that cause genomic instability in the nuclear genome.

The most reasonable explanation for the results of the experiments listed above is that for malignant transformation of cells, genetic changes in nuclear DNA are insufficient, if at all necessary. It seems that the malignant transformation of cells is the result of defects in the cytoplasm, and not defects in the nucleus *. When mitochondria function normally, then carcinogenic mutations in nuclear DNA have little chance of being realized. Healthy mitochondria can reverse the cancerous behavior of cells even with mutated nuclear DNA, and vice versa, mitochondrial dysfunction will force cells to increase glycolysis and fermentation, inducing cells with normal DNA to malignant transformation.

The tumor phenotype can be returned to the normal phenotype not only at the cellular level. The state of the tissue and, by and large, the whole organism is decisive in the question of whether a tumor will form or not, and what will be its fate. Tissue with fully differentiated cells is able to successfully influence the behavior of emerging malignant cells towards their correction.

Transplantation of cancer cells into healthy tissue can lead to the loss of their malignant properties, despite the presence of mutations * *. Not only a single cancer cell, but even a sufficiently large group of cancer cells have no chance of forming a tumor if the tissue into which they are implanted is healthy. In order for a human to form a tumor, a simultaneous injection of at least 10 million cancer cells * is required. When too few cancer cells are introduced from a tumor into healthy tissue, they completely lose their malignancy and turn into normal cells * *, although this should not be the case with irreversible genome defects.

Finally, cancer cells, under certain microenvironmental conditions, are able not only to stop their growth, but also to turn to a normal phenotype * *. Such cases are called spontaneous remission. All of these facts somehow do not agree well with the prevailing theory that cancer comes from a single mutated cell that has lost control, and that its development is irreversible.

The ever-growing body of evidence strongly suggests that the current view of the origin and nature of cancer needs to be revised. That the tumor is more of a metabolic than a genetic disease *. And that the mitochondrial metabolic theory (MMT) can better explain the signs of cancer than the somatic mutation theory (SMT) *.

From the point of view of metabolism, it is the pathological violation of cellular respiration that is the center of the problem. It is it that precedes *, and is the cause of the instability of the genome, which accompanies the process of tumor development. While short-term genomic instability may not be sufficient for genetic mutations, long-term instability increases this risk. Among the nuclear DNA mutations that have arisen, there may be those that contribute to further metabolic disorders, malignant transformations, and disease progression.

Targeting an anti-cancer strategy at a genetic problem, which guides modern medicine, does not make practical sense. In decades of research, no single specific causative gene or set of genes has been identified for the vast majority of cancers. Mutations in cancer cells occur in millions of unpredictable places in DNA, giving each case its own personality. And, in terms of genetics, each of them may require individual treatment. Meanwhile, tumor cells will acquire more and more new mutations. Finally, cancer cells can exist without any mutation at all.

At the same time, the mitochondrial problem is common to almost any case of cancer. Cells with poorly functioning mitochondria may not be cancerous. However, it is unlikely that there will be cancer cells with fully functional mitochondria. From it point of view, the treatment of most cases of cancer can be reduced to a common protocol.

If the defect in tumor cells really lies in the mitochondria, and not in the cell nucleus, then this completely changes the approach to cancer treatment. Instead of, or at the same time, focusing on the destruction of cells with irreversibly mutated genes, one should focus on restoring the normal functioning of mitochondria in all cells of the body.

Normalization of cellular respiration.

Living mechanisms have an inherent desire for organization, orderliness and development, while non-living mechanisms have an inherent desire for chaos, disorder and destruction. The chemistry of living nature differs from the chemistry of inanimate nature in that the processes in it proceed in a controlled manner, with the help of appropriate enzymes and the coordinated work of electrochemical mechanisms. However, the control of biochemical reactions requires energy costs, so no living organism can exist without energy supply.

The main part of the energy produced by human cells is extracted from glucose molecules. First, glucose is transported into the cell and participates in a process called glycolysis. This is a multi-stage biochemical process that takes place in the cytosol of the cell. Each of the ten metabolic reactions of glycolysis requires specific enzymes and does not require oxygen. Glycolysis does not break down the glucose molecule to the end, and therefore does not release all the energy available in it.

As a result of glycolysis, 2 molecules of pyruvate (pyruvic acid) are formed from 1 molecule of glucose and 2 molecules of adenosine triphosphate (ATP) are charged with energy, which is used by all cells of the body as an energy agent. The resulting pyruvate from glycolysis can then be metabolized to lactate and excreted from the cell as metabolic waste. Most primitive life forms produce energy in this way, and they did it long before oxygen appeared in the atmosphere of the planet (about 2.5 billion years ago). Such unicellular organisms also have such characteristics of cancer cells as uncontrolled division and immortality.

Cells of highly organized organisms have the ability to break down pyruvate further, forming only water and carbon dioxide as metabolic waste products. This is done in cellular organelles called mitochondria, first in a cyclic biochemical process called the Krebs cycle (KC) and then in an electrochemical process called oxidative phosphorylation (OP). In such cells, from each glucose molecule, 2 ATP molecules can be produced, as before, using glycolysis, and up to 36 additional ATP molecules using OP. The latter process requires the consumption of oxygen, which serves here as an electron acceptor in the final stage of energy production – the so-called «electron transport chains».

In human cells, more than 90% of intracellular ATP is produced precisely by OP *. Despite the fact that OP needs an oxygen supply, this mode of energy production is many times more efficient than glycolysis. Surprisingly, some cells in the human body continue to use glycolysis as their main source of energy (eg, erythrocytes, retinal cells, testis cells). These are normal glycolytic cells. However, all other normal cells, including epithelial cells, use OP as the main energy generator.

Impaired cellular energy metabolism is a defining characteristic in almost all cancers. If in normal epithelial cells the vast majority of all energy is produced by mitochondria, then in cancer cells, mitochondria largely lose their function. This not only radically changes the picture of energy metabolism. During the various stages of glycolysis, chemical raw materials are formed as metabolic waste products, which make it possible to build a daughter cancer cell from it. The more intense glycolysis, the more such building material, the faster the cancer cell can divide.

So, in most cases, cancer cells are characterized by increased glycolysis – the conversion of glucose into pyruvate and further increased metabolism of the resulting pyruvate into lactate. Many normal cells during hypoxia can also temporarily increase enzymatic energy production, but when adequate oxygen levels are restored, they always return to mitochondrial energy production. Cancer cells do not, however, use glycolysis even in the presence of sufficient oxygen (a phenomenon called aerobic glycolysis).

The increase in energy production through fermentation is not only a consequence of the previous stages of the development of the tumor process, but also the cause of its subsequent stages. Long-term dependence of cells on enzymatic energy production exhibits cancerous cell characteristics such as genomic instability, intracellular metabolic disturbance *, acid-base reversal *, loss of differentiation, and uncontrolled growth *. Thus, enhancement of mitochondrial respiration of cells has an important therapeutic value * *.

The restoration of natural cellular metabolism includes two complementary actions: the weakening of anaerobic respiration and the strengthening of aerobic respiration.

It is believed that several hundred million years ago they were taken up by an ancient glycolytic host cell, but were not internalized and were instead incorporated into its intracellular processes, providing the cell with significant evolutionary advantages. Further, this symbiont cell became the progenitor of all living organisms whose cells use OP.

The main cellular function of mitochondria is the production of energy necessary for the metabolic processes of the cell. The energy source for the cells of the human body can be various nutrients, but ultimately this energy is stored only in a molecule called adenosine triphosphate (ATP). ATP is used for energy by all cells, both healthy and cancerous.

Mitochondria not only produce energy, but also take part in a number of other extremely important cellular functions. This is the regulation of membrane potential and differentiation; cell signaling through reactive oxygen species (ROS); calcium signaling, control of apoptosis and autophagy; regulation of cellular metabolism; regulation of iron metabolism and heme synthesis; regulation of steroid synthesis *. Thus, the health of the cell and the whole organism depends on the health of mitochondria.

Mitochondria undergo specific structural and functional changes in cancer, and they are actively involved in metabolic reprogramming. A decrease in the number of mitochondria and/or their functionality is considered a characteristic feature of cancer cells. Of course, loss of mitochondrial function is not always associated with malignant transformation; other conditions are required for such a switch, but malignant transformations are almost always associated with loss of mitochondrial functions.

In the process of ATP production in mitochondria, a large number of free radicals (oxidants) appear, such as reactive oxygen species (ROS) and reactive nitrogen species (APA). The more raw materials for energy enter the mitochondria, and the more actively it is produced, the more free radicals are formed, the stronger their destructive effect. And it is not so important whether energy is produced from glucose, lipids or amino acids, their total amount is important.

The resulting free radicals damage any proteins, primarily the mitochondria itself, which leads to degradation of the inner layer of its membrane and disruption of the process of oxidative phosphorylation. Therefore, even with a large amount of incoming raw materials, energy production through the OP can fall. The unprocessed excess of raw materials accumulates in the cell, clogging its internal space. Oxidative stress in mitochondria also causes instability of the mitochondrial and even nuclear genome and enhances the expression of oncogenes. In addition, high levels of oxidants trigger a cascade of events that decrease proteasome activity, decrease telomere length, and impair immune function.

Since the formation of free radicals is as natural in the process of energy production as the formation of smoke when burning wood, natural defense mechanisms are provided in the cell to neutralize them. This is, first of all, glutathione, which is the most powerful intracellular antioxidant. Insufficient production of glutathione, or its depletion due to a large number of oxidants, or both, will lead to the degradation of OP.

In addition to oxidative damage, mitochondria can experience other aggressive attacks that lead to a weakening of the RP process, and to a further increase in the level of free radicals and other mitochondrial toxins. This further exacerbates the situation, dispersing the destructive vicious circle *. At the same time, mitochondrial functions, including the production of ATP, are naturally suppressed, which entails the most serious consequences.

Mitochondrial toxicity can be induced by some drugs, through various mechanisms such as mitochondrial DNA depletion (eg, nucleoside reverse transcriptase inhibitors), inhibition of fatty acid beta-oxidation (eg, valproic acid), opening of mitochondrial permeability transition pores (eg, anthracyclines), creation of oxidative stress and mitochondrial glutathione depletion (eg, acetaminophen), uncoupling of electron transport from ATP synthesis (eg, tamoxifen), and inhibition of mitochondrial electron transport chain complexes (eg, statins) *.

A significant part of the energy produced by mitochondria is spent on the work of ion pumps built into the cell membrane *, which maintain a balance between intracellular ions (potassium and magnesium) and extracellular ions (calcium and sodium). The quantitative difference between sodium and potassium ions on both sides of the cell membrane creates a certain electrical potential on it, which supports many cellular functions.

Due to the lack of energy, the efficiency of sodium-potassium membrane pumps decreases. The intracellular level of sodium ions relative to potassium ions increases, which negatively affects the function of cell membranes. Due to the imbalance of sodium and potassium ions, the electrical potential on the membrane of the transforming cell decreases, creating an increasingly negative field around it. This worsens the functional state of the cell. In addition, such a cell acquires the ability to repel negatively charged drugs and cells such as red blood cells and lymphocytes, preventing oxygen and the immune system from counteracting the tumor.

Another part of the cell's energy is spent on the synthesis of enzymes, thanks to which the chemical reactions inside the cell become controlled. The lack of certain enzymes further impairs CK and RP. When the supply of glucose and other sources of energy to the cell is sufficient, but the mitochondria are not able to provide the necessary level of energy, the cell is forced to turn to an older and less profitable principle of energy production, increasing glycolysis and fermentation *. And this is one of the first steps of the malignant degeneration of the cell.

A deep energy deficit forces the production of only those enzymes that are needed only for the survival of the cell. With a decrease in energy supply, such cellular functions of mitochondria as differentiation, inhibition of cell growth, and apoptosis deteriorate. Through apoptosis, abnormal cells are removed, thereby preventing the cancer process. If apoptosis does not work well, then such cells can remain alive and reproduce offspring with the same defective mitochondria.

In addition, the cell of a multicellular organism must coordinate its behavior with other cells. She does this by capturing the slightest nuances of the concentration of chemical signals and electric fields. The operation of such sensory mechanisms also requires energy consumption. The stronger the energy deficit in the cell, the worse the communication of the cell, the less it responds to social demands, the weaker it responds to the signals restraining unbridled growth, the deeper it plunges into the selfish behavior of its single-celled ancestor, the more it acquires cancerous signs.

Both poorly functioning mitochondria and a small number of them contribute to switching the cell phenotype to a malignant one. In cancer cells, there may actually be an increase in the number of mitochondria in order to compensate for the loss of their functions in this way *. However, such efforts are not capable of fundamentally solving the energy problem until its fundamental causes are eliminated. Without this, mitochondria, even with a large number of them, will remain defective.

Thus, long-term dysfunction of mitochondria, manifested as a lack of oxidative phosphorylation, in combination with increased glycolysis and glutaminolysis, can lead the cell to enter a steady state of unrestrained proliferation – with further loss of differentiation, with resistance to apoptosis, and with other characteristic features signs of a cancer cell.

Mitochondrial dysfunction is a telling signal of aging and a feature of virtually all degenerative diseases *, not just cancer * *. More and more deteriorating work of mitochondria as the years go by is observed not only in humans, but also in other animals. However, we can improve mitochondrial health to some extent. Mitochondrial respiration can be enhanced in several ways, such as by reducing oxidative stress; an increase in the number of mitochondria; normalization of their metabolism; the ability to replace defective components; mitophagy and apoptosis *.

Certain supplements * * may help improve mitochondrial function. They are able to reduce oxidative load, provide additional opportunities for oxidative phosphorylation, strengthen leaky mitochondrial membranes, and remove non-functional mitochondria.

Cofactors and antioxidants:

Vitamins and minerals:

Lipids and transporters:

Mitochondrial modulators:

Combinations of some of the above agents have been clinically tested. In one two-month study, patients with intractable chronic fatigue improved fatigue scores by a third when taking membrane phospholipids (2'000 mg/day), CoQ10 (35 mg/day), microencapsulated NADH (35 mg/day), L-carnitine (160 mg/day), α-ketoglutaric acid (180 mg/day), as well as lipids and other additives * *.

Physical activity. Mitochondrial functionality can be improved and maintained by stimulating autophagy, as well as by reducing calorie intake and moderate physical activity * *.Indeed, an increase in physical activity leads to increased autophagy * * and an increase in energy levels, which means more efficient functioning of mitochondria. This stimulates cells to increase the number and quality of mitochondria.

Additionally, stress-reducing practices such as meditation or yoga, as well as adequate sleep, may be helpful. A healthy diet, detoxification, and reduced inflammation and associated oxidative stress also protect mitochondria from chemical damage that reduces mitochondrial DNA copy number and ATP production. Techniques for reducing inflammation levels will be discussed in the «Anti-inflammatory therapy» section †.

Emotional condition. It seems incredible, but one study reported an association between positive emotions and the ability of mitochondria to produce energy *. Increased positive mood increased the enzymatic activity of the mitochondrial respiratory chain, as well as the number of copies of mitochondrial DNA. People's psychological state in the 3 days before blood was drawn predicted their mitochondrial health index, but not vice versa, suggesting a cause-and-effect relationship.

In this case, the mitochondria of immune cells (leukocytes) were studied, which may be directly related to their ability to destroy pathogens. But, as one might assume, the mitochondrial health of other cells in the body can also depend on a person’s emotional mood through a complex system of hormonal and other cellular communication.

Restriction of energy resources. The mitochondria of cancer cells are unable to produce sufficient levels of energy due to structural and/or functional abnormalities *. And although cancer cells significantly increase energy production through glycolysis, mitochondrial energy production is still critical for them. A further decrease in the energy of cancer cells can lead to their death, and the tumor – to a decrease in the growth rate.

The results of more than 30 years of research convincingly prove that calorie restriction is probably the most powerful and widely used nutritional intervention to suppress the process of carcinogenesis *. Metabolic nutrient overload causes defragmentation of the cell's mitochondrial network, while intermittent fasting induces autophagy, which removes dysfunctional mitochondria.

It can be reasonably assumed that excess calories and lack of oxygen significantly weaken the inhibition of cell proliferation and accelerate the formation of a cancerous cell phenotype. On the other hand, a lack of calories and sufficient oxygen inhibits cell growth and stimulates autophagy, which removes poorly functional organelles and cells, including cancer cells.

Indeed, theoretical models show that increased tissue fueling leads to rapid onset of cancer cell hallmarks such as rampant growth and tissue invasion *. If in the absence of glucose the competitive advantage is on the side of the cells with more economical aerobic respiration, then in the case of an abundance of glucose it is on the side of the cells with faster anaerobic respiration *.

In other words, unlimited resource conditions promote the spread of the cancer phenotype, while limited resource conditions prevent it. Based on this fundamental position, energy hunger should not only reduce the risk of cancer, but also contribute to the suppression of cancer cells and incline them to mitochondrial respiration.

Indeed, limiting the supply of raw materials for energy production to cells significantly slows the growth and development of many types of cancer, including breast cancer *. This reduces not only the level of insulin, but also the level of growth factor IGF-1, which stimulates the metabolism and growth of tumor cells *. While any therapeutic agent targets one or more targets, cellular energy restriction covers a range of therapeutic targets, including inflammation and angiogenesis * *.

We can limit the energy resources of cells using the following methods:

Reducing the volume and calorie content of food. Caloric restriction can cause the suppression of many of the genes and metabolic pathways that regulate glycolysis *. The Physiological Minimum recommended by The Office of Disease Prevention and Health Promotion for women of average build is ~ 1'600 kcal/day *, however, this value should be adjusted depending on age, height, index body weight and level of physical activity *. At a given minimum level, the maximum daily caloric intake should not exceed 2'400 kcal/day. It is this range of daily calorie values that is associated with the lowest morbidity rates *.

However, even a low-calorie diet should be adequate. If the food cannot provide sufficient levels of essential substances, they will have to be taken in the form of supplements. This is especially true for riboflavin, nicotinamide, pantothenic acid, other vitamins and enzymes involved in michondrial function.

Since fats have the highest calorie content, and carbohydrates have the least, it is easiest to reduce calories consumed at the expense of fat.

Decreased intake of carbohydrates in the body. There are several weight loss drugs based on the principle of reducing the absorption of carbohydrates from food.

Gluconeogenesis inhibition (inhibition of glucose production in the liver).

Depletion of blood glucose levels due to its increased consumption. Muscle cells use glucose as their main energy source, while brain neurons use it as their sole source of energy. An increase in physical and mental activity will thus increase the consumption of glucose and reduce the level of insulin in the blood. In turn, consistently low glucose and insulin levels will help maintain optimal mitochondrial health.

It has been noted that under conditions of hypoxia, mammary gland cells accumulate a large supply of energy in the form of glycogen, which contributes to the protection of cells from oxidants and proliferation. Moreover, the more aggressive the tumor, the more glycogen accumulates in it *. The specific glycogen stores in an aggressive tumor can be comparable to those in the liver. Disabling the ability to use this energy with glycogen phosphorylase (an inhibitor of the enzyme responsible for breaking down glycogen) makes cancerous cells much less aggressive *. It is noteworthy that only the isoform of the enzyme that is characteristic of the brain, and not the liver, is effective here. Despite the temptation of such a proposal, its clinical application is still very far away.

Limiting the entry of glucose into the cell. Glucose is transported into cells by either the passive membrane transporters GLUT or the ATP-dependent and sodium-dependent transporter SGLT. By paralyzing the work of these transporters, it is possible to reduce the flow of glucose into the cell. Several herbal remedies are known to be able to moderately inhibit glucose transporters in vitro.

It would be logical to limit the flow of glucose into cells. But under the condition of a high concentration of glucose in the blood, insulin will strongly protest against such a decision. Because its job is to lower the blood glucose by pushing it into the cells. If we can make it difficult for glucose to be imported into the cells, both glucose and insulin levels in the blood can be high. That is, we will create the symptoms of type II diabetes. This means that it is possible to resort to limiting the entry of glucose into the cell only if its concentration in the blood is within safe limits.

Suppression of the process of glycolysis in cells reduces the amount of raw materials for energy production. As already mentioned, a lack of pyruvate will slow down the division of cancer cells, and a serious deficiency of it will cause cell death.

Currently, a limited number of specially designed glycolysis inhibitors are used, and all of them have certain disadvantages.

Suppression of alternative metabolic pathways for energy production. Despite the significant dependence of cancer cells on glycolysis, its suppression has little effect on curbing tumor growth. Limiting glucose intake has its limits, and besides, glucose is not the only source of raw materials for the production of ATP. With an insufficient amount of glucose, cells are able to use alternative, less efficient energy sources, mainly amino acids and lipids. Cells in general show an extraordinary ability to extract energy from available material, including lactic acid *, ketones * and as yet unknown sources *.

Decreased production of ATP from glutamine. Proliferating/glycolytic cells easily switch from glucose to amino acid feedstock, predominantly glutamine.

Glutamine can be used by cells for mitochondrial energy production through oxidative phosphorylation. Just like other sources of energy, glutamine enters the mitochondria, where it participates in a series of closed enzymatic reactions called the Krebs cycle (KC). The molecules formed during this cycle are electron donors for the process of oxidative phosphorylation (OP). During OP, energy is accumulated in the phosphate bonds of the ATP molecule, and then spent on the needs of the cell.

Ideally, from 1 glucose molecule that enters the cell (from 2 pyruvate molecules), you can get energy for 38 ATP units; of these, 8 are in the process of glycolysis (2 directly and 6 indirectly), 6 are in the process of converting pyruvate to acetyl-CoA, and another 24 are in the process of OP. As a final metabolite, 6 molecules of water and 6 molecules of carbon dioxide are formed. Although cancer cells are usually OP disabled due to a poorly functioning electron transport chain, the efficiency of the Krebs cycle enzymes is preserved in them. Therefore, glutamine gets a chance to charge ATP molecules by the so-called substrate phosphorylation in the segment of succinyl-CoA → succinate (FTP) transformations. There is no need for oxygen in this reaction.

Why glutamine and not any other amino acid? First, it is the most abundant amino acid in the body. And secondly, because of the peculiarities of its metabolism. While other amino acids can also provide energy production, glutamine is the only amino acid that does not require energy to be converted metabolically into succinyl-CoA *. Because of this, compared to other amino acids, glutamine provides the highest efficiency in energy production, and for a cancer cell, saving energy is critical.

Thus, cancer cells can obtain a fairly large amount of energy by fermenting glutamine. And, as experiments with glioblastoma cancer cells have shown, they intensively use this opportunity *. Therefore, glucose fasting will be a weakly effective therapy if this alternative energy source is not blocked *.

The strategy of limiting the supply of cells with glutamine may have varying success depending on the subtype of breast cancer. Luminal-type cells are glutamine-independent, while basal-type cells are glutamine-dependent *. Thus, glutaminase inhibitors may be more effective against the most aggressive subtypes, TNBC and HER2+ basal-like breast cancer, but not against ER+ luminal cancer *.

Unfortunately, lowering glutamine levels is more problematic from a practical point of view than lowering glucose levels. Avoiding animal protein and dairy products, as well as plants such as spinach, beans and kale, could help to some extent in solving this problem. However, plant foods contain not only glutamine, but also many other useful nutrients, and its restriction will lead to food inferiority.

In addition, protein and glutamine are also required by normal cells, not just cancer cells. In particular, glutamine is actively used by macrophages, T- and B-cells of the immune system; as well as intestinal cells. In addition, glutamine is required for the transmission of impulses by brain neurons. Therefore, we can only talk about limiting certain foods and changing the structure of the diet in terms of reducing protein intake to a physiological minimum. Since glutamine can be synthesized from other amino acids, and by non-cancerous cells of the tumor itself, it may be worth limiting the intake of any protein during therapy. And perhaps even all these efforts will not be enough if we do not use glutaminolysis inhibitors.

Production of ATP from lipids. Fatty acids as a fuel for the production of ATP are widely used by cells of the liver, kidneys, muscles, as well as cells of adipose tissue.

In conditions of glucose deficiency, the cells of many other organs and tissues can also resort to lipid metabolism. For example, during prolonged fasting, ketone bodies, which are released into the blood by liver cells during fatty acid metabolism, can be used as fuel molecules. In the end, fat was stored for this, in order to use its energy on a «rainy day».

The accociation between fat intake and cancer risk will be discussed in more detail in the «Diet Therapy» section †. But we must understand that the degree of negative impact of fat on cancer depends on the caloric content of the diet. After all, the cell doesn't care where it gets its energy from, and so total calorie restriction may be more important than the choice of calorie sources.

Although the metabolic pathways for energy production from glucose, amino acids, and fatty acids begin differently, they eventually converge into a common place, the Krebs cycle, and must end in oxidative phosphorylation. Of all the major energy sources (glucose, lipids and amino acids), only glucose is the most efficiently fermentable feedstock. Less effective, but rather competitive, is glutamine. Other energy sources are much less efficient, as they require energy for their metabolism.

A cancer cell can to some extent compensate for a decrease in energy intake in the form of glucose with an energy intake in the form of glutamine. Because both glucose and glutamine are fermentable raw materials. At the same time, ketone bodies (acetoacetate and β-hydroxybutyrate) are not fermentable raw materials. They require oxidative phosphorylation to generate energy. They enter the mitochondria and are included in the Krebs cycle already in the form of succinate, bypassing the metabolic segment of substrate phosphorylation (succinyl-CoA → succinate) *. In addition, the inclusion of ketone bodies in the Krebs cycle can be expected to reduce the cell's use of glutamine because they will compete for the same enzymes in subsequent steps in the Krebs cycle.

But what if we cut off the supply of cells with both glucose and glutamine, and instead of these two sources of energy, supply them with ketone bodies, and in a minimal amount? Then energy production will drop in both normal and cancerous cells. However, normal cells retain the OP mechanism in a sufficiently functional state, which ensures a high ATP yield. Therefore, they can more easily endure an energy crisis by generating energy from ketone bodies. At the same time, cancer cells and other cells with a degraded OP mechanism will be subjected to deadly metabolic stress.

Moreover, in this case, cancer cells will not have to rely on the help of other cells of the tumor microenvironment. Those will not be up to help, they themselves will be in a state of crisis, and compete for the same resources. Therefore, cancer cells will be in a less favorable position in terms of survival and will be forced to stop growing. Cells with the most dysfunctional mitochondria will suffer more than others, and may end their lives in apoptosis.

From such considerations follows the tempting proposal to change the structure of food intake in such a way as to radically reduce the intake of metabolizable carbohydrates and proteins, but increase the intake of fatty acids. Of course, with a minimal reduction in total calorie intake. So-called the ketogenic diet, which will be discussed in more detail below † is based on this theoretical principle. In some clinics, the ketogenic diet is used to a limited extent as an additional therapy, as well as to enhance the therapeutic effect of chemotherapy following this diet.

Dr. Thomas Seyfried * proposed treatment strategy, which he called Press-Pulse, seems reasonable. Here, energy pressure is first applied to the cancer cell (Press). For this, a ketogenic diet is used, in which the overall energy intake is reduced as much as possible. If carbohydrate reduction is used to block glycolysis, then glutaminolysis inhibitors are used to block glutaminolysis. As a result, the enzymatic production of cellular energy drops sharply, severely cutting off the energy supply of the cancer cell *.

Thus, the growth of the cancer cell is suppressed. However, the energy received from the OP may still be enough to keep it alive. Therefore, next step is the impact of chemotherapy (Pulse). In a severe energy crisis, a cancer cell simply does not have the strength to pump toxins out of the cell, and it becomes very vulnerable to chemotherapy. In this way, the dosage of toxins and their negative consequences for the entire body can be reduced. True, such a protocol requires very fine regulation, which is achievable only in a clinical setting.

Decreased production of ATP from aldehydes *. Ketone bodies produced by the liver from fatty acids can be metabolized into aldehydes, and aldehydes can be metabolized by the enzyme aldehyde dihydrogenase (ALDH1) into carboxylic acid. The latter reaction produces NADH, which may be another source of energy for ATP production *.

Suppression of the production of fuel raw materials inside the tumor. Cancer cells are not the only type of cells that form a tumor. Some of the cells in the tumor microenvironment can convert lactate secreted by glycolytic cells back into pyruvate, which can again be used as fuel by cancer cells. Unfortunately, no way has yet been proposed to avoid this way of feeding cancer cells. Neutralization of lactate in the extracellular space by intratumoral alkaline injections, such as baking soda, looks like an overly adventurous method.

Correction of pyruvate metabolism. Normalization of cellular respiration involves an increase in mitochondrial ATP production, and at the same time suppression of the enzymatic one. While limiting the fuel supply will limit energy production and induce the cell to use it more efficiently, this indirect enforcement will probably not be enough. To force a cell to return to mitochondrial respiration, one has to turn to direct coercion methods.

Inhibition of pyruvate fermentation. Pyruvate is metabolized to lactate by the enzyme lactate dehydrogenase. Neutralization of this biochemical reaction interrupts the metabolic pathway of ATP production characteristic of cancer cells, thereby depriving them of a significant part of their energy.

A double blow to the energy supply of cancer cells (fermentation + weak mitochondria) can bring them to the brink of existence. Therefore, a combination of all the above activities looks more effective.

Activation of the movement of pyruvate into mitochondria. If the fermentation of pyruvate to lactate is blocked, then the pyruvate obtained as a result of glycolysis can be used by mitochondria for oxidative respiration. The problem, however, is not only that the mitochondria themselves do not work well, but that there may be obstacles to the penetration of pyruvate into the mitochondria. For example, the enzyme pyruvate dehydrogenase kinase (PDK) present in the cell inhibits the entry of pyruvate into the mitochondria. There are 4 isotypes of PDK (PDK1-PDK4), and among them, PDK3 has the highest enzymatic activity and is the only enzyme that is not inhibited by high concentrations of pyruvate.

The figure presented here shows all the efforts proposed above to correct the metabolism of a cancer cell in order to put it before a choice: switch to mitochondrial respiration or die.

If mitochondrial DNA mutations prevent a cell from fully utilizing OP, it will be difficult for it to survive. It cannot be said, however, that this method will be sufficiently successful.

Firstly, a general (instead of local) effect on cells will depress the energy of all other cells in the body, not just cancer cells. This, of course, can heal the body as a whole, rejecting cells with poorly functioning mitochondria and keeping regenerating cells from the final transition to glycolysis. However, there are many normal cells in the body that use only glycolytic ATP production. Strong inhibition of glycolysis will affect the work of cells such as red blood cells or retinal cells. Whereas we should only target cancer cells.

Secondly, the delivery of therapeutic substances into the tumor in a natural way is difficult. And their introduction directly into the tumor is not always possible. But even if this problem is solved, we return to the first point: the tumor does not consist only of cancer cells. We cannot selectively deliver active substances to our target – cancer cells, they will also come to normal cells that form tumors. For example, immune cells. And we cannot predict how their functionality will change from our actions.

Thus, manipulation of the metabolism of tumor cells has its definite limit. Nevertheless, it can make a significant contribution to the antitumor fight, being included in the complex therapy.

All attempts to increase the oxygen respiration of tumor cells may be unsuccessful if the main participant in this process, oxygen, is deficient.

Low oxygen concentration is a key factor in the high acidity in the tumor and the activity of the tumor process. Lack of oxygen enhances glycolysis in cells and causes malignant transformation of their phenotype (Warburg effect). Conversely, the presence of oxygen causes the suppression of glycolysis (Pasteur effect).

Increasing oxygen concentration in tissue. Tumor hypoxia poses a serious obstacle to effective cancer therapy *. For example, the main mechanism of radiation therapy is the creation of a high concentration of reactive oxygen species; therefore, oxygen deficiency gives hypoxic tumors a much higher radiation resistance. Many chemotherapy drugs also lose their therapeutic efficacy under hypoxic conditions. Finally, hypoxia reduces the effectiveness of immunotherapy. Thus, an increase in oxygen concentration due to a decrease in acidity in the tumor microenvironment and an increase in oxygen delivery to the tumor are extremely important factors in antitumor therapy.

Decreased acidity in tissues will be discussed separately in the «Acid-Alkaline Balance» section †. And the concentration of oxygen in the blood can be increased in several ways:
- With the help of natural carriers (erythrocytes). Lack of oxygen can be caused by both low red blood cells and a lack of hemoglobin, which reduces the ability of red blood cells to carry oxygen. The latter can be caused by a deficiency in the diet of chemical elements (zinc, iron) and nutrients (vitamin B12, folate), poor absorption, kidney failure, blood loss and other reasons.
- With the help of synthetic carriers. In addition to red blood cells, alternative oxygen carriers in the blood can be used, but they still remain difficult to access.
- By increasing blood flow. Increasing blood circulation, for example by vasodilation, improves its ability to deliver oxygen *, minerals and nutrients, and also improves the effectiveness of both therapeutic agents and the prevention of metastasis. To do this, you can use both physiotherapy and some supplements, for example, vasodilators. Deterioration of blood circulation can be caused by high aggregation of red blood cells and microthrombosis, which may require additional efforts.
- By directly dissolving oxygen in the blood. Increasing the oxygen concentration in the blood directly, bypassing the carriers, can be done by inhaling a gas with a very high oxygen content – both at normal atmospheric pressure and at elevated pressure (hyperbaric oxygenation). The latter requires special equipment and the services of qualified personnel.

The last point needs further clarification. Prolonged breathing with pure oxygen can bring not only benefits, but also harm. First, oxygen without the addition of carbon dioxide causes blood vessels to constrict. Thus, it is possible not only not to increase, but, on the contrary, to weaken the delivery of oxygen. Secondly, oxygen is prone to the formation of reactive oxygen species (ROS), which have a destructive effect on any proteins in our body.

It is also worth remembering that prolonged exposure to vasodilators increases the supply of not only oxygen, but also energy sources – glucose and glutamine. If glycolysis and glutaminolysis are not suppressed at the same time as increased blood circulation, this can contribute to the advancement of cancer, which again emphasizes the need for a comprehensive approach to cancer treatment.

Local hyperthermia (41-42 °С) enhances the movement of fluid in the tumor and weakens the resistance of cancer cells to radiation therapy *. Hyperthermia may improve oxygenation of hypoxic breast tumors *. The effect of hyperthermia can last for a day after the session *.

Although the combination of hyperthermia and standard treatment may enhance the therapeutic effect, there is no consensus regarding the use of hyperthermia outside the course of treatment due to the lack of knowledge of this topic. There is a danger that increased circulation of fluid may contribute to the spread of tumor cells. A similar risk applies to massage, infrared and ultrasonic irradiation of the tumor zone. Thus, hyperthermia can only be considered as a therapy in combination with other therapies.

Proteolytic enzymes are enzymes that help break down protein. Their activity is regulated in such a way that they destroy foreign, dead or non-functional protein structures without affecting the functional cells of the body.

Proteolytic enzymes improve blood flow by cleaning the walls of blood vessels and reducing the level of fibrinogen *, which also reduces blood pressure *. They cleanse both the blood itself and the cells contained in it from fibrin and mucus, and thereby expose antigens on the surface of cancer cells to the immune system, reducing the risk of metastasis. Of the entire set of proteolytic enzymes, only a few have been sufficiently studied.

Different enzymes are most active at different levels of acidity, and therefore a complex containing trypsin, chymotrypsin, bromelain, papain, serrapeptase will apparently be more versatile than any of these enzymes alone. An example of such a complex is Wobenzim™. Dosage: 600-1'000 mg/day, but not more than 4'000 mg/day *. Long-term use without interruption is allowed, but caution should be exercised. The combination of proteolytic enzymes and their high dosage enhances the effect of other anticoagulants, which in many cases can be very dangerous.

NSAIDs are non-steroidal anti-inflammatory drugs.

Another aspect of the antitumor activity of NSAIDs, such as celecoxib, is the ability to directly inhibit mitochondrial respiration, transmembrane electrical potential and ATP production, causing an excess of ROS, triggering apoptosis of cancer cells, and also reducing the ability of cancer cells to migrate * *.

Dibazol is a well-known vasodilator. Dibazol relaxes the muscles of the walls of blood vessels, improving blood circulation. In addition, it acts as a weak immune system stimulant. Unlike acetylsalicylic acid, dibazol does not cause acidification of body tissues. Dosage: 3×20 mg 2 hours before or 2 hours after meals.

Vitamin B3 (vitamin PP, niacin, nicotinic acid, nicotinamide) expands small blood vessels (including the brain), improving blood microcirculation. It has a weak anticoagulant effect, normalizes blood cholesterol, and also has detoxification properties. The dosage for healthy people is 20 mg/day. Overdose up to 100 mg/day is not harmful.

Arginine (3×700 mg) is an essential acid capable of producing nitric oxide (NO), which causes smooth muscle cells to relax. As a result, blood vessels dilate, increasing blood flow and improving oxygen delivery to tissues.

Flax-seed. In mice, the consumption of ground flaxseed (10% of the total diet) during tamoxifen therapy resulted in a decrease in the density of microvessels in the tumor and a decrease in the release of the pro-inflammatory cytokine IL-1 *. The combination of flaxseed and tamoxifen inhibited grafted tumor size by more than 53% in mice compared to tamoxifen alone *.

Some plants improve blood circulation in small vessels and capillaries.

Known platelet inhibitors are inositol, ginseng, turmeric, ginger, flaxseed oil, fish oil, vitamin E. Caution should be exercised in their use, however, because excessive inhibition of platelets can cause internal bleeding as well as internal bleeding. Reception of the funds discussed above should be stopped starting 2 weeks before the operation, and resumed no earlier than 1 week after the operation, in agreement with the doctor.
Considering that the above means enhance the effect of each other, when they are taken together, the dosage should be significantly reduced.

Reducing oxygen demand. An alternative and perhaps more effective solution to the problem of hypoxia is not to satisfy the cellular demand for oxygen, but to reduce this demand. Reducing oxygen consumption by cells reduces its depletion in the tissue, thereby increasing oxygen saturation. Computer simulations show that a 30% reduction in oxygen consumption is as effective at reversing hypoxia as a 4-fold increase in blood flow *. For this, the following means can be used:

It is important to understand that in addition to the forced increase in the oxygen level in the tumor, many physiological factors also influence the oxygen level in the tumor tissue. Thyroid hormones, for example, play a major role in metabolic activity and oxygen uptake by cells. Higher levels of the T4 hormone are associated with a higher risk of any type of cancer, including breast cancer *. Thus, the health of the thyroid gland strongly affects the oxygen saturation of the tissue and the effectiveness of antitumor therapy.

Next chapter