Prospects for complex mitochondrial therapy in oncology

The aim of the study: Brief overview of the background, current status and possibilities of mitochondrial therapy of malignant tumors.

Complex mitochondrial therapy becomes step by step an important area in the prevention, treatment and rehabilitation of oncological diseases. Considering the main components of this approach, the following aspects can be highlighted:

• 1.    The leading role of mitochondria in carcinogenesis has been clearly revealed. Studies, starting with the pioneering works by O. Warburg (1), show that mitochondria play a key role in the development and progression of cancer. They make an influence on the initiation and growth of tumors, the survival and death of cancer cells, and modulate the processes of metastasis. At the same time, multidirectional changes in the number of mtDNA molecules in cells, changes in the total mitochondrial mass, alterations in the dynamics of mitochondrial biogenesis, regulation of mi-toptosis and apoptosis, redox homeostasis and tumor metabolism are observed [2].

• 2.    Most cancers are characterized not only by aerobic glycolysis (the “Warburg effect”) and glutamino-lysis, but also by altered balances of other metabolites

  18 | Cardiometry | Issue 33. November 2024

• 3.    New data from genetic studies show that most malignant tumor genomes are extremely heterogeneous. The high degree of genetic heterogeneity hinders attempts to exploit genomic defects for effective therapy. Moreover, most genetic alterations in tumors are thought to be secondary to mitochondrial dysregulation in energy metabolism [3]. In contrast to the genetic heterogeneity of nuclear DNA found in tumors, most, if not all, tumor cells share a common metabolic characteristic, aerobic glycolysis, resulting from abnormal oxidative phosphorylation. According to these data, cancer can be characterized as a systemic metabolic disorder determined by the state of the mitochondria.

• 4.    All tumor cells deviate from the norm in the content or composition of cardiolipin, a lipid of the inner mitochondrial membrane, where oxidative phosphorylation occurs. Aerobic cells with cardiolipin abnormalities cannot effectively use OXPHOS and, therefore, increase energy production by fermentation. This fact cannot be overemphasized, given that tumor cells can have normal OXPHOS values. The cardiolipin changes found in tumor cells support the Warburg’s theory.

• 5.    The results of numerous experiments on the transfer of nuclear DNA and mitochondrial DNA in normal versus cancer cells indicate indisputably that multiple mutations of nuclear DNA, and instability of the nuclear genome as a whole, are not the cause, but the consequence of the primary mitochondrial changes [4]. Normal mitochondria can suppress oncogenesis, whereas abnormal mitochondria enhance the latter.

such as lactate, pyruvate, and ketones. These secondary metabolites are essential for cancer cell growth and proliferation, but they cannot fully satisfy the energy needs of a growing tumor.

PRESS-PULSE STRATEGY

OF MITOCHONDRIAL THERAPY

There are three pathways known for cellular ATP synthesis: 1) Glucose fermentation provides ATP and precursors for lipid and nucleotide synthesis, as well as glutathione. 2) Glutamate, derived from glutamine, provides ATP synthesis via the TCA cycle. 3) Phosphorylation at the substrate level of the TCA cycle via succinate thiokinase can generate significant amounts of cellular ATP under hypoxic conditions, especially in tumor cells with defective respiration. Glutamate, a derivative of glutamine, is also used to produce glutathione, which protects tumor cells from oxidative stress.

Thus, simultaneous suppression of mitochondrial glucose and glutamine metabolism deprives tumor cells of their ability to produce energy by locking their ability to synthesize proteins, lipids and nucleotides. At the same time, increased levels of non-fermentable ketone bodies, calorie restriction, and a ketogenic diet provide normal cells with an alternative energy source instead of glucose, protecting them at the same time from oxidative stress.

Defects in the mitochondrial respiratory chain prevent tumor cells from using ketone bodies to synthesize ATP. It is known that resistance to nutrient deficiency in the normal cells is higher than that in the tumor cells, since the normal cells have a flexible metabolism and are able to quickly switch from glucose to ketone bodies when the glucose level decreases. Consequently, the glycolysis-dependent tumors are less adaptable to metabolic stress than the normal tissues that allows using nutritional stress to suppress the energy metabolism of tumor cells. In addition, energy stress helps restore the microenvironment around the tumor, reversing pro-oncogenic changes in the mutation-free cells.

Apoptosis under energy stress is higher in tumor cells than that in normal cells. Multiple genetic defects in tumor cells reduce the adaptive response capabilities of the nuclear genome that increases the likelihood of their death under the conditions of energy deficiency with a decrease in the glucose level and an increase in the level of ketones. No matter which mutations are involved in tumor initiation and progression, the reduced metabolic adaptation capabilities make tumors vulnerable.

The “Press-pulse” therapeutic strategy for the gradual suppression and destruction of cancer cells was proposed by Vincent [5]. For this purpose, a long-term hypocaloric ketogenic diet is first initiated, inducing chronic metabolic stress in the tumor, suppressing its aggressiveness. Synergistic cyclic use of medical drugs that disrupt glucose and glutamine metabolism creates additional periodic, pulsating metabolic pressure, elevating the apoptosis of cancer cells. Against this background, the effectiveness of all pro-oxidative modalities increases: ozone therapy, hyperbaric oxygen therapy, interval hypoxic therapy, creating another factor of pulsed action, causing an increase in ROS predominantly in the tumor cells rather than in the normal cells, thus contributing to the death of cancer cells due to oxidative-reductive stress.

A synergistic anticancer effect of the glycolysis inhibitor 2-deoxyglucose (2-DG) was found in combination with a ketogenic diet [6]. At the same time, 2-DG monotherapy in combination with a standard diet was ineffective, but showed a powerful therapeutic effect when used simultaneously with a ketogenic diet. In addition to 2-DG, a number of other glycolysis inhibitors (3-bromopyruvate, oxaloacetate, and lonidamine) can also produce a synergistic therapeutic effect.

In the given case, the ketogenic diet is a factor of constant pressure on cancer cells, while 2-DG and other inhibitors, as well as pro-oxidative methods make their pulsed effects, which are used cyclically to avoid toxicity.

It has been found that hyperbaric oxygenation (HBO) increases the effectiveness of the ketogenic diet, reducing tumor aggressiveness and suppressing metastasis. The mechanism of this action is based on elevating oxidative stress and lipid peroxidation in cells. The effect of the combination of HBO and keto diet can be enhanced by the introduction of exogenous ketones that further suppresses tumor growth and metastasis. In addition, intravenous infusions of vitamin C and sodium dichloroacetate (DCA) can also provide a pronounced extra oncolytic effect.

The glutaminase inhibitor DON (6-diazo-5-oxo-L-norleucine) has demonstrated its therapeutic effects in the clinic, provided that its toxicity is controlled. DON is most effective in combination with glycolysis inhibitors such as lonidamine. Other glutaminase inhibitors (bis-2-(5-phenylacetamido-1,2,4-thiadi-azol-2-yl), ethyl sulfide, may also be effective in targeting glutamine-dependent tumors.

Since glutamine is particularly essential for the im-munocytes function, it may be reasonable to schedule intermittent glutamine supplementation to maximize the therapeutic benefit while protecting immune system function.

A recently developed glucose-ketone index and the glucose-ketone index calculator (GKIC) have been successfully used to assess the potential therapeutic effect of different ketogenic dietary regimens in cancer treatment [7]. GKIC is a simple tool that measures the ratio of glucose to ketones in blood. The GKI values of 1.0 and below are considered to be effective, although the therapeutic benefits appear to be more related to an increased amount of ketone bodies with insulin reduction in parallel rather than to glucose reduction alone. GKI may serve as a simple indicator for assessing the therapeutic efficacy of different diets in a wide range of cancer diseases.

CONCLUSION

Emerging evidence suggests that cancer is a mitochondrial metabolic disorder that is completely dependent on glucose and glutamine availability for tumor cell growth and survival. The Press-pulse therapeutic strategy aims to reduce the availability of glucose and glutamine to tumor cell mitochondria, thereby increasing the tumor vulnerability to oxidative stress, mitophagy, and apoptosis. A low-carbohydrate, high-fat ketogenic diet combined with glycolysis inhibitors suppresses the glycolytic and pentose phosphate metabolic pathways necessary for the synthesis of ATP, lip- ids, glutathione, and nucleotides. Glutamine inhibitors suppress tumor cell proliferation by depriving them of glutamine, which is necessary for the Krebs cycle and the synthesis of glutathione, nucleotides, and proteins. Additional pro-oxidative effects (ozone, HBO, hypoxic therapy) combined with a ketogenic diet with restricted carbohydrate calories stimulate mitophagy, apoptosis, and produce an antiangiogenic effect, while simultaneously suppressing regional and systemic inflammation. The Press-pulse paradigm is an effective saving mitochondrial therapeutic strategy for the effective treatment of the vast majority of malignancies with minimal toxicity, as this approach specifically inhibits the key energy pathways responsible for tumor cell growth and survival while enhancing the energy efficiency of healthy cells and tissues.