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Molecular Medicine: Current Aspects

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Research Article

Mechanisms of Cancer Growth and Metastasis with Substantiation of New Methods Cancer Therapy

Ponizovskiy MR

Correspondence Address :

MR Ponizovskiy
Kiev Regional p/n Hospital
Kiev Region, Vasilkov District, Voksalna str. 8
Ukraine
Tel: 0038-04471-3-12-03
Email: ponis@online.de

Received on: July 29, 2017, Accepted on: August 02, 2017, Published on: August 10, 2017

Citation: Ponizovskiy MR (2017). Mechanisms of Cancer Growth and Metastasis with Substantiation of New Methods Cancer Therapy

Copyright: 2017 Ponizovskiy MR. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract
The shift of balance catabolic processes and anabolic processes into excessive anabolic processes causes Warburg effect mechanism of cancer metabolism. Excessive anabolic processes lead to disbalance between catabolic processes and anabolic processes that exerts proliferative mechanisms of cancer cells displaying mechanisms of cancer metabolism. Taking into account mechanisms cancer metabolism, it was explained mechanisms cancer growth and metastasis. Besides it was substantiated mechanisms of cancer treatment via combination "Prolonged medical starvation" with considerably decreased dosage of cytotoxic drugs and also substantiated advantage of this method of cancer therapy in comparison with cancer treatment using great dosage of cytotoxic drugs. Just the use method "Prolonged medical starvation" with decreased dosage of cytotoxic drugs prevents recurrence cancer disease and resistance to anticancer drugs, in comparison with intensive anticancer chemotherapy with great dosages of cytotoxic drugs in modern methods cancer chemotherapy. Also it was described and explained mechanism of the method prevention supplementary new metastases in processes of up-to-date chemotherapy.
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Keywords: Anabolic endergonic processes, Catabolic anaerobic exergonic processes, Catabolic aerobic exergonic processes, Warburg effect, Reactive Oxygen Species (ROS)

Introduction
Stationary State of open non-equilibrium non-linear thermodynamic system of an able-bodied organism is characterized by stability of Internal Energy [the temperature 36,0⁰C - 36,9⁰C by which all enzymes operate etc.] and Internal Medium [stable concentrations of substances in blood and neurolymph] according the first law of thermodynamics [1]. Stationary State of open thermodynamic system of an able-bodied organism displays balance catabolic exoergonic processes & anabolic endoergonic processes. Quasi-stationary pathologic States of an open thermodynamic system of an organism in inflammatory processes are characterized by shift of balance catabolic processes & anabolic processes into excessive catabolic exergonic processes [2]. Quasistationary States of an open non-equilibrium non-linear thermodynamic system of an organism in cancer diseases are characterized by shift of balance catabolic processes & anabolic processes into excessive anabolic endergonic processes displaying Warburg effect mechanism [2,3]. Different balances catabolic exergonic processes & anabolic endergonic processes cause different chemical potentials in extracellular and intracellular mediums inducing different charges on inner cellular membrane and outer cellular membrane displaying mechanism cellular capacitors operation [4]. Just operations of cellular capacitors are the supplementary mechanism maintenance stability Internal Energy of an organism [the temperature 36,6⁰C - 36,9⁰C by which all enzymes operate etc.] according first law of thermodynamics [1,4]. Interactions between all cells of an organism and between cells and an organism occur as the results of cellular capacitors operations via production resonance waves for remote reactions across distance on strange object, intruded into an organism [4]. Thus interactions between cellular capacitors of an organism's cells maintain common stability of Internal Energy and Internal Medium both in cells and in an organism [4]. Also there were explained differences between mechanisms production superoxide [O2 *-] in mitochondria of normal cellular cycle and in mitochondria of oncologic cells which displays as mitochondrial mechanisms exerting processes replication as well as supplemental mitochondrial mechanism in oncogenesis [5]. The mechanism DNA replication and production complex ROS/H2O2/free radicals in mitochondrial function of both normal cellular cycle and oncologic cellular cycle were explained from the point of view of the offered concepts [5,6]. Just it was offered concept of mechanism exerting nuclear proliferative processes by ROS/H2O2/free radicals that causes neutralization ROS/H2O2/free radicals in proliferative processes [5]. This concept gave possibility to explain interactions between nucleus and mitochondria as in normal cells and as well as in cancer cells [1,5]. Also it was offered method of cancer treatment via combination "Prolonged medical starvation" with considerably decreased dosage of cytotoxic drugs which suppress cancer metabolism leading to cancer depression that promotes efficient cancer therapy [7-9]. The offered method of cancer treatment does not intrude into Internal Energy and Internal Medium of an organism and does not damage immune and hormonal system of an organism causing prevention recurrence cancer disease and resistance to anticancer drugs, in comparison with intensive anticancer chemotherapy with great dosages of cytotoxic drugs in modern methods cancer chemotherapy. The mechanism of offered method cancer treatment suppress cancer metabolism via the targeting Warburg effect mechanism [7-9]. Taking into account mechanism of cancer growth and metastasis, it was also offered the method prevention supplementary new metastases in processes of up-to-date chemotherapy [10]. Also it is substantiated advantage of mechanism cancer treatment via combination "Prolonged medical starvation" with considerably decreased dosage of cytotoxic drugs over the modern methods chemotherapy.

The Mechanism of Warburg Effect [3] (Figures 1 and 2)
Affecting nuclear DNA by v-oncogene, cellular metabolism is mutated via oncogenesis tissue due to shift normal balance anabolic processes & catabolic processes into excessive anabolic processes. As the result of enormous anabolic processes in cancer tissue and the enormous consumption of energy and Acetyl-CoA for anabolic (biosynthetic) processes, it occurs the overload of "nodal point of bifurcation anabolic and catabolic processes" [NPBac] causing partial suppression catabolic processes because of the remained lack Acetyl-CoA for catabolic anaerobic processes. However some of catabolic processes remain for cancer cells survival. The increase of lactic acids production is the necessary endergonic mechanism accumulation energy for huge anabolic processes in condition glycolysis metabolism and enormous consumption of energy for anabolic processes in cancer tissue. On the one hand, increase of Lactic acids, as the main marker of glycolysis, displays increase glycolysis inducing by AKT in cancer metabolism. On the other hand, partial suppression catabolic anaerobic processes of oxidative phosphorilation violates normal balance catabolic anaerobic processes & catabolic aerobic processes due to prevalence aerobic processes over anaerobic processes. Thus increased glycolysis and prevalence aerobic processes form Warburg effect which is characterized by "Aerobic Glycolysis" in cancer tissue metabolism. As compared with cancer tissue metabolism, able-bodied tissue metabolism displays Pasteur effect which is characterized by "incompatibility glycolysis with aerobic oxidation". Common balance anabolic processes & catabolic anaerobic processes & catabolic aerobic processes is maintained in able-bodied tissue. Just it occurs identical direction of flow energy between catabolic pathways of aerobic processes and anaerobic processes (Glycolysis and Krebs cycle) in able-bodied tissue. Therefore Lactic acids, as the marker of Glycolysis, is not defined simultaneously with aerobic oxidation reflecting mechanism of Pasreur effect [incompatibility glycolysis with aerobic oxidation]. Common balance anabolic processes & catabolic anaerobic processes & catabolic aerobic processes is violated in cancer tissue due to excessive anabolic processes with partial suppression catabolic anaerobic processes and prevalence aerobic processes over anaerobic processes as well as increased quantity of Lactic acids, i.e. Glycolysis. Just the increased quantity Lactic acids (marker of Glycolysis) accumulating energy for excessive anabolic processes and partial suppression catabolic anaerobic processes in cancer tissue exhibit simultaneously expressed aerobic oxidation and Glycolysis, i.e. "Aerobic Glycolysis" of Warburg effect. Thus Warburg effect mechanism as "Aerobic Glycolysis" is formed in cancer tissue metabolism [2,3] (Figure 1). Besides mitochondria aerobic oxidative function, due to cytochrome system operation [cytochrom C, cytochromc- oxidase, cytochrom P450 etc.], deliver stable quantity Oxygen (O2) via Hemoglobin system in blood corresponding to stable Respiratory Index [CO2/O2 = 0,8 - 1,0] in an organism. The normal common balance anabolic processes & anaerobic processes & aerobic oxidative processes displays production of some quantity Reactive Oxygen Species (ROS) in mitochondria due to remained some unused oxygen ion [O-] after anabolic processes and anaerobic processes in able-bodied tissue, The excessive shift balance aerobic oxidative processes & anaerobic processes of oxidative phosphorilation into aerobic oxidative processes, owing to partial suppression of anaerobic processes of oxidative phosphorilation, causes production of excessive quantity Reactive Oxygen Species (ROS) in mitochondria of cancer cells. Just remaining surplus quantity oxygen ion (O-), unused in anaerobic processes of Krebs cycle, adds electron and is transformed into mitochondrial superoxide [O2 *-] which reduces Ferric iron [Fe3+] into Ferrous iron [Fe2+] with oxygen:

1) O2 + e− → O2*-; 2) O2*- + Fe3+ → Fe2+ + O2. Then superoxide anion is subjected to dismutation by manganese superoxide dismutase (MnSOD) and copper, zinc superoxide dismutase (Cu, ZnSOD) converting into hydrogen peroxide:

2) 2O2*- + 2H+ = H2O2 + O2In mitochondrial matrix the normal steady concentration of superoxide [O2 *] is higher than in cytoplasm and nucleus. Thus it is formed complex ROS/ H2O2/free radical, and it is happened Haber-Weiss-Fenton reaction of iron catalyzed by superoxide transformations which is passed into Fenton reaction [5,6] (Figure 2).

3) Fe3+ + O2*- Fe2+ + O2

 Fe2+ + H2O2 Fe3+ + OH + *OH

 O2*- + H2O2 OH + *OH + O2 + Fe3+

The hydrogen peroxide [H2O2] from ROS is detoxified by mitochondrial Glutathione Peroxide (GPX) and Phospholipid Hydroperoxide Glutathione Peroxide (PHGPX): Glutathione (GSH) is transformed into oxidized Glutathione (GSSG) in the reaction of reducing H2O2 into H2O which is stimulated by glutathione peroxide. Furthermore mitochondrial isoforms of peroxiredoxins such as peroxiredoxin-III and V utilize some molecules of cysteine to reduce H2O2 into H2O and return glutathione peroxide to its reduced state. The formed complex ROS/H2O2/free radical pass through mitochondrial membranes and cytoplasm into nucleus and exerts superoxide [O2 *] for inducing free radicals (*OH). Free radicals (*OH) react on nuclear DNA [nDNA] and induce process replication via realizing of 2nDNA reaction in G2 phase of cellular cycle [5,6]:

4) *OH + H2-nDNA-DNA --> H2O + H*-nDNA-DNA;

 O*+ 2H2O --> 2H* + 2OH;

 2H*-nDNA-DNA + 2H* --> 2nDNA-H* + 2nDNA-H*;

 2nDNA-H* + 2*OH --> 2nDNA + H2O

The free radicals (*OH and H.) induce nDNA replication and also are neutralized in G2 phase of cellular cycle causing nDNA replication as in cancer cells as well as in normal cells [5,6,11-15]. Just it occurs moderate replication in G2 phase cellular cycle due to moderate quantity Free radicals operation in able-bodied tissue. However it occurs excessive replication in G2 phase cellular cycle due to excessive quantity Free radicals operation in cancer cells which induce replication by considerably greater quantity. Free radicals than in normal cells because of considerably more quantity ROS/H2O2/free radicals production in cancer cells [5,6,11-15]. Just these great quantity ROS/H2O2/free radicals induce irrepressible proliferative processes of cancer cells [5,6,11-15].

Highlight of Cancer metabolism
Catabolic anaerobic processes of glycolysis carry out peculiar functions as the primer for both anabolic endergonic processes and catabolic exergonic processes of oxidative phosphorilation as in stationary state of able-bodied cells as well as in quasistationary state of cancer cells, providing their survival. The pathway of catabolic anaerobic processes of glycolysis is divided into anabolic processes and catabolic processes of Krebs tricarboxylic acids cycle in "Acetyl-CoA nodal point of bifurcation anabolic and catabolic processes [NPBac]" and generate energy, which is accumulated into Lactic acids for anabolic processes.
As outcome of oncogenes operation the huge anabolic processes cause huge consumption of energy and Acetyl-CoA and partial suppress catabolic processes in cancer tissue. The formed Lactic acids accumulate great quantity energy for huge anabolic processes in condition glycolisis metabolism in cancer tissue. The excessive anabolic processes partial suppress catabolic anaerobic processes remaining the part of catabolic oxidative phosphorilation of Krebs Tricarboxylic Acids Cycle (TCA) for cancer cells survival which promote Apoptosis Resistance characterized cancer cells. Besides Krebs Tricerboxylic Acids Cycle (TCA) generates supplemental considerable quantity energy for maintenance stability Internal Energy in cancer tissue [stable temperature 36,6C - 37,5C by which all enzymes operate]. The prevalence aerobic oxidative processes over the partial suppressed anaerobic processes of oxidative phosphorilation and expression glycolysis display mechanism "aerobic glycolysis" of Warburg effect in cancer tissue [2,3,5]. Interactions between all cells of an organism occur due to remote reactions as the results of cellular capacitors operations via production of related resonance waves [4,13]. Just interactions between cellular capacitors of cells are the supplementary mechanism to the biochemical mechanism of three levels for maintenance stability of Internal Energy and Internal Medium both in organism's cells and in an organism [4,13,16,17]. As compared with able-bodied cells of an organism, cancer cells are not related to cells of an organism, and an organism's cells don't make remote reaction via resonance waves of their capacitors on cancer cells [4,13,18]. Thus it occurs autonomic operation of cancer cells and cancer tumor.

The Mechanisms of Cancer Tumor Growth and Metastases
The overload of "nodal point of bifurcation anabolic and catabolic processes" [NPBac] with partial suppression catabolic exergonic anaerobic processes occurs due to shift balance anabolic endergonic processes & catabolic exergonic anaerobic processes into excessive anabolic endergonic processes in cancer metabolism. Thus this violated balance anabolic processes & catabolic anaerobic processes cause violation balance catabolic aerobic processes & catabolic anaerobic processes due to prevalence aerobic processes of respiratory oxidation over partial suppressed anaerobic processes of oxidative phosphorilation in cancer metabolism. The prevalence aerobic processes of respiratory oxidation over anaerobic processes of oxidative phosphorilation leads to disbalance between mitochondrial aerobic respiratory function and anaerobic oxidative phosphorilation of link Glycolysis - Krebs Tricarboxylic Acids Cycle (TCA). Just mitochondrial aerobic oxidative function produces stable quantity Oxygen ions [O-2] via operation of cytochrome system [cytochrom C, cytochrom-c-oxidase, cytochrom P450 etc.] in cancer cells because of delivering stable quantity Oxygen (O2) by Hemoglobin system in blood corresponding to stable Respiratory Index [CO2/O2 = 0,8 - 1,0] in an organism. Produced in Krebs tricarboxylic acids cycle (TCA) Hydrogen ions (H+) react with Oxygen (O2) and form Water (H2O) that must eliminate Oxygen from liquids of an organism and cells of an organism [10]. However the supplementary Oxygen (O2) does not find sufficiently Hydrogen ion (H+) to react with Oxygen (O2) and does not produce supplementary Water (H2O) [5,10,18]. Therefore this supplementary Oxygen (O2) adds electron, due to Reactive Oxygen Species (ROS) operation, and is transformed into superoxide (O2 *) which generates free radicals. Free radicals exert DNA replications in G2 phase of cellular cycle via inducing reaction 2nDNA replication (5, 6). Partial suppression catabolic processes of Krebs tricarboxylic acids cycle (TCA) decreases quantity of Hydrogen ions (H+) production in cancer metabolism. The great insufficiency of Hydrogen ions (H+) production causes abundance superoxide (O2*) inducing excessive quantity of ROS/ H2O2/free radicals which exert accelerative DNA replications via inducing accelerative reaction 2nDNA reactions in cancer cells [5,10,18].

*OH + H2-nDNA-DNA --> H2O + H*-nDNA-DNA;

 O*+ 2H2O --> 2H* + 2OH;

 2H*-nDNA-DNA + 2H* --> 2nDNA-H* + 2nDNA-H*;

 2nDNA-H* + 2*OH --> 2nDNA + H2O

The free radicals (*OH and H.) induce nDNA replication in G2 phase cellular cycle, and also the free radicals (*OH and H.) are neutralized in final G2 phase of nDNA replication as in cancer cells as well as in normal cells [5,6]. Then it occurs M phase of cellular cycle, i.e. Mitosis in cell division. Thus moderate cellular replication occurs in norm due to production moderate quantity ROS/H2O2/free radicals in able-bodied cells and occurs via G○, G1/S, G2, M phases cellular cycle. The accelerated cycle of cancer cell is induced by accelerated cycle of v-oncogene initially and then is continued via affecting cancer nuclei by excessive quantity ROS/H2O2/free radicals produced in cancer cells' mitochondria. The accelerated cellular cycle of cancer cells leads to shortening cancer cellular cycle without G○ and G1 phases cellular cycle that creates excessive cellular replication of cancer cells. The perpetual affecting cancer cells by excessive quantity of ROS/H2O2/free radicals cause irrepressible cancer tumor growth which also supports by some growth factors as EGF, FGFs, HGF, HDGF, GDF9, IGFs and so on [5,6]. Furthermore the irrepressible cancer tumor growth leads to partial suppression catabolic oxidative processes due to overloaded "nodal point of bifurcation anabolic and catabolic processes" [NPBac] with consumption great quantity energy and Acetyl-CoA that impede excretion via oxidative destruction of great quantity high-molecular substances being produced by excessive anabolic processes of cancer metabolism. Therefore the excretion of great quantity high-molecular substances, produced via huge anabolic processes occurs within cancer cells (Figure 1). These cancer cells with great quantity high-molecular substances in them move from cancer tissue to able-bodied tissue without overload of "nodal point of bifurcation anabolic and catabolic processes" [NPBac] and exerting catabolic processes for oxidative destruction great quantity high-molecular substances. Just these movements of cancer cells with great quantity high-molecular substances are exerted by cellular capacitors of able-bodied cells causing remote reactions across distance via resonance waves on these high-molecular substances. Thus there are formed metastases. Besides the partial suppression catabolic processes due to overload "Nodal point bifurcation anabolic and catabolic processes [NPBac]" and lack Acetyl-CoA in cancer tissue touches also on Krebs Tricarboxylic Citric Acids cycle [TCA] via partial suppression mechanism transferring Oxaloacetates from cancer tissue TCA to cancer cells' TCA [18] (Figures 3 and 4). The partial suppressed mechanism transferring Oxaloacetates from cancer tissue TCA to cancer cells' TCA violates link between cancer tissue TCA and both cancer cells' mitochondrial TCA and cancer cells' mitochondrial cytochrome system. Thus overload NPBac with partial suppressed mechanism transferring Oxaloacetates from cancer tissue TCA to cancer cells' TCA results in expression mechanism metastasis due to blocking oxidative destruction of synthesized high-molecular substances in cancer tissue [10,18] (Figures 3 and 4). Also operations of an organism cells' cellular capacitors via resonance waves promote movement cancer cells with the synthesized high-molecular substances within them to healthy tissue without overload "Nodal point bifurcation anabolic and catabolic processes [NPBac] and lack of Acetyl-CoA" for oxidative destruction high-molecular substances and cause metastases.

The Mechanism Operation "Prolonged Medical Starvation 42 - 45 days" in Cancer Therapy [7-9] (Figure 5)
The "Prolonged medical starvation 45 days" leads to activation catabolic processes in an organism for maintenance stable temperature 36,0C - 37,0C by which all enzymes operate [7-9]. Cancer tumor is situated inside the human organism using the organism as Environment, and obtains the substances from depot of an organism for its metabolism (fat depots, carbohydrate depots etc.). Also an organism obtains substances from depots of an organism for its metabolism in condition of treatment by "Prolonged medical Starvation (during 42-45 days)" [7-9]. The treatment by "Prolonged medical Starvation (during 42-45 days)" causes considerable decrease almost of all depots (especially fat depots) of an organism and also exhausts an organism's fat and carbohydrate depots, that leads to the competition between cancer tissue and an organism for the use of remained decreased depot in order to maintain the normal temperature (36,0⁰C - 37,0⁰C) by which all enzymes operate. The aerobic exothermic oxidation generates the greatest quantity calories promoting suppression of anabolic endergonic processes in the condition of the treatment by "Prolonged medical Starvation during 42-45 days" as in the organism as well as in cancer tissue. It occurs for maintenance stability of the normal temperature
(36,0C - 37,0C), i.e. Internal Energy of an organism [7-9]. Thus this competition between the organism and the cancer must lead to the win for most strong one. But the protective forces of the organism become stronger due to support with herbal extracts, delivering vitamins and microelements into the organism [8,9,19]. Also increase of fat metabolism from fat depot leads to augmentation glutathione peroxide (GPX) and phospholipid hydroperoxide glutathione peroxidise (PHGPX) in all cells of an organism and contributes to neutralization of redundant ROS/H2O2 in G1/S phases cellular cycle of cancer cells, that causes suppression excessive proliferative processes in G2 phase cellular cycle of cancer cells [7-9]. Thus "Prolonged medical Starvation" promote suppression DNA replication due to neutralization of excessive ROS/H2O2/free radicals in G1/S phases cellular cycle before G2 phase cellular cycle of nDNA replication as in an organism and as well as in cancer cells [5,7- 9]. The decreased anabolic endergonic processes in condition of "Prolonged medical Starvation" influences on nuclear DNA [nDNA] replication due to violation balance between chemical potentials of cytoplasm (μcytopl) and blood plasma (μplasma) [4,13]. Just eliminating partial suppression of anaerobic processes of oxidative phosphorilation by "Prolonged medical Starvation" restores normal balance aerobic oxidative processes & anaerobic processes of oxidative phosphorilation in mitochondria of cancer cells that causes decrease of Reactive Oxygen Species (ROS) in mitochondria of cancer cells and normalization of quantity ROS/ H2O2/Free radicals, eliminating excessive proliferative processes with accelerating irrepressible cellular cycle of cancer cells [5,13]. Thus the suppression of excessive nucleus DNA replication causes normalization of cellular cycle in cancer cells and cessation of irrepressible proliferative processes with irrepressible cancer tumor growth.
Thus such basic phenomena of the cancer metabolism are inhibited [7-9]:
a) Mechanism of "Warburg effect".
b) Biochemical and biophysical mechanisms of metastases.
c) The phenomenon of "absence inhibition of contact cell propagation in the metabolism of malignant tumor" and as well as irrepressible tumor growth causing depression of cancer metabolism.
Just inhibition of Warburg effect by "Prolonged medical Starvation" leads to cancer depression.
Thus "Prolonged medical Starvation" contributes to depression of cancer tumor metabolism that helps for efficient anticancer therapy with considerably decreased dosage of cytotoxic drugs [8,9]. Such approach to anticancer chemotherapy prevents damage Internal Energy and Internal Medium both an organism and cells of an organism, preventing damage of immune and hormonal systems as the links of defensive mechanism in regulative system of an organism. Stable immune and hormonal systems as the links of system stability Internal Energy and Internal Medium an organism prevents both recurrence of cancer disease after long anticancer chemotherapy and resistance to anticancer drugs which occurs due to intensive anticancer chemotherapy with great dosage of cytotoxic drugs. Just great dosage of cytotoxic drugs intrudes into Internal Energy and Internal Medium violating immune and hormonal systems of an organism.

The Mechanism Operation the Extracts of Herbs in the Cancer Treatment via "Prolonged Medical Starvation during 42-45 days" [19]
Considering the above described mechanism operation of the treatment by "Prolonged medical Starvation during 42-45 days", this method of cancer treatment leads to depression of development tumor as the result of damage the main mechanisms of cancer tumor metabolism. The crucial role of maintenance Internal Energy stability of the organism in condition of Prolonged medical Starvation appertains to the all tendered extracts of herbs as well as to the Vegetable Juice Mixture, which deliver to an organism necessary microelements and vitamins, especially folic acid, that is necessary for hemopoiesis, and decreases also excessive acidification in the blood of the organism. It must especial pay attention on the extract of red cranesbill (Geranium robertianum) which contains significant amounts of Vitamins A, B and C as well as such minerals: calcium, potassium, magnesium, iron, phosphorus, germanium, according to Shipard Isabell [20]. Also Shipard Isabell notes that Geranium (or Herb Robert) has wide range of clinical applications as remedy with such properties: antibiotic and antiviral properties, sedative property, tonic, astringent, diuretic, digestive, antioxidant [20]. Helfer et al. show effect of Geranium on HIV-1 as antiviral remedy [21]. Besides, folk healer R. Breuss notes that red cranesbill (Geranium robertianum) contains the small quantity of radium [22,23]. It should be paid attention on especial importance that Geranium (or Herb Robert) contains germanium and radium. Also taking into account that red cranesbill (Geranium robertianum) has antibiotic and antiviral properties, it can assume that red cranesbill (Geranium robertianum) has also light cytotoxic property as concerning to germanium and radium which cytotoxic properties do not raise the doubts. Thus it can assume that red cranesbill (Geranium robertianum) causes light cytotoxic property on depressed malignant tumor in condition of Prolonged Starvation 42 - 45 days, promoting cancer therapy, and cures of patient. Such light cytotoxic property can not make negative influence on immune and hormonal systems of an organism essentially as opposed to chemotherapy with great dosage cytotoxic drugs (Figure 5). 

The Results of Practical Observations [8,9,19]
The author was convinced of the efficiency of this method treatment by the meetings with more than 100 cured patients during 2 years, who were treated by folk healer Omelchenko who used "Prolonged medical Starvation 45 days with extracts of herbs and small quantity cytotoxic herb":
Austrian folk healer Breuss R. used for treatment "Prolonged medical Starvation during 42 days" and described a lot of the patients with various locations of Cancer tumor and with various locations of metastases, who were cured by this method of treatment [22,23]. The data, described by austrian folk healer Breuss R, concerning results of this method treatment were also convinced author in efficiency of this method treatment [22,23].
Also the author was also convinced on own experience the efficiency of treatment the ill man with the incurable cancer stage [7-9,19]:
At 1998 the patient Ch. has been operated for Cancer of the left kidney (the kidney was resected).
24.02.1999 it was detected by the X-ray inspection in the "Kiev Oncologic dispensary" the diagnosis: Metastatic cancer the intermediate bronchus of the right lung, IY degree, clinical stage IY. 
After detail examines the patient Ch. has been discharged from Oncologic dispensary how the incurable patient, and he has agreed to receive Prolonged medical starvation treatment with the examinations in the "Kiev Institute of roentgenology, radiology and oncology".
At 24.02.1999 the patient was examined in the "Kiev Institute of roentgenology, radiology and oncology" before Prolonged medical starvation treatment. Histological examination of a sputum from a bronchus: The fragment of necrotic masses of a disintegrating malignant tumour and a clump of polygonal cells of a tumor of not forming complexes and frames is detected in the stuff. The histological pattern mismatches a lung carcinoma but specifies in the metastasis from the tumor of kidney (hypernephroma). The result of X-ray inspection was: Metastatic cancer the intermediate bronchus of the right lung IY degree, clinical stage IY. The diagnosis is remained the same how Oncologic dispensary.
The treatment was occurred from 01.03.1999.
The examination after Prolonged medical treatment: On X-ray patterns there are not found pathological changes in the lungs. The medical examinations of the patient during three years (catamnesis) and the examination in 2002 at the "Kiev Institute of roentgenology, radiology and oncology" show that the patient was cured.

The Method Prevention Supplementary New Metastases in Processes of Modern Methods of Chemotherapy
There were some theories which explain mechanism of cancer metastasis based on the low expression of K+ in the Kv channel of malignant tumors [24-26] and also the role of mitochondrial frataxin protein in mechanism of cancer metastasis [27]. Considering role Krebs Tricarboxylic Citric Acids cycle (TCA) in processes suppression mechanism transferring Oxaloacetates from cancer tissue TCA to cancer cells' TCA in cancer metabolism, the use citric acids from citric juice exerts expression Krebs Tricarboxylic Citric Acids cycle (TCA) and increases Acetyl-CoA eliminating overload "Nodal point bifurcation anabolic and catabolic processes [NPBac]" and partial suppression catabolic anaerobic processes. Elimination overload NPBac with partial suppression catabolic anaerobic processes contributes to prevention additional metastasis in processes of up-to-date chemotherapy. Really excessive quantity of citric acids with appropriate enzymes in citron increases quantity Acetyl-CoA due to mechanism maintenance stable index of Equilibrium Constant reaction in Krebs tricarboxilic acids cycle [10,18]: Acetyl-CoA + Oxaloacetate ↔ Citric acid (Figures 4 and 6). This reaction in Krebs Tricarboxylic Acids Cycle [TCA] moves right saving stable Equilibrium Constant of the reaction Acetyl-CoA + Oxaloacetate → Citric acid. However this reaction moves left via increase Acetyl- CoA in condition increased quantity citric acid for saving stable Equilibrium Constant of the reaction Acetyl-CoA + Oxaloacetate ← Citric acid. Increased quantity of Acetyl-CoA eliminates overload "Nodal point bifurcation anabolic and catabolic processes [NPBac]" and partial suppression catabolic anaerobic processes that contributes to prevention additional metastasis in processes of up-to-date chemotherapy. Also increase Acetyl-CoA, as currier K+ ions, eliminates the low expression of K+ in the Kv channel of cancer tumor [24-26] that prevents new metastases [10,18]. Beside increased quantity citric acids exert Citric Acids cycle causing expression of catabolic anaerobic processes that stimulates also catabolic aerobic processes via mitochondrial frataxin protein operation with cytochrome c inhibiting cancer metabolism and preventing supplementary cancer metastasis in processes of up-to-date chemotherapy [10,18,27]. There are the clinical observations [10,18]: I have treated the sick man whom was found the multiple metastases in visceral peritoneum. The sick man has refused himself from the offered alternative therapy of "Prolonged medical starvation during 45 days with small dosage cytotoxic remedy" and has chosen up-to-date chemotherapy with Fluorouracil and Erbitux immunotherapy. Taking into account the above described mechanisms of the role citric acids in Citric acids cycle, I have recommended him to use citric juice from the squeezed two citrons by day which should be diluted in 1 litre water for prevention intestine irritation due to great concentration of citric acids. This method must be used simultaneously with chemotherapy as the supplementary method for prevention new metastasis. The patient has drunk the citric juice, in which the enzymes for Citric Acids cycle are preserved, during two months. Then patient has drunk the citric juice from the squeezed one citron daily which was diluted in 1 litre water. The weekly examinations showed that there were not found new metastasis by the patient during the period of two years. The state of the patient is satisfactory.

Discussion
The some theories explain mechanism of cancer metastasis based on the low expression of K+ in the Kv channel of malignant tumors [24-26] and also the role of mitochondrial frataxin protein in mechanism of cancer metastasis [3,27]. The above explained mechanism of Warburg effect gives possibility to explain the mechanism metastasis in following mode [3]: The huge anabolic processes block excretion from cancer tissue of synthesized highmolecular substances via oxidative destruction them because of overload "Nodal point bifurcation anabolic and catabolic processes [NPBac]" and lack of Acetyl-CoA for oxidative processes (Figure 1). Therefore the excretion of synthesized high-molecular substances occurs within cancer cells which move to healthy tissue without overloaded "Nodal point bifurcation anabolic and catabolic processes [NPBac]" and having sufficiency of Acetyl- CoA. These cancer cells are carried by lymph or blood causing cancer metastasis. Really expression of mitochondrial frataxin occurs due to overload "Nodal point bifurcation anabolic and catabolic processes [NPBac]" and lack Acetyl-CoA which promotes partial suppression anaerobic oxidative phosphorilation and causes prevalence aerobic oxidative processes over anaerobic oxidative phosphorilation in mitochondria. Just the overload NPBac and lack Acetyl-CoA leads to expression of mitochondrial frataxin because of overload NPBac and prevalence aerobic oxidative processes over anaerobic oxidative phosphorilation in mitochondria [3,27]. Besides the low expression of K+ in the Kv channel of malignant tumors is induced by overload "Nodal point bifurcation anabolic and catabolic processes [NPBac]" and lack Acetyl CoA, which is the carrier of K+ ions in Kv channel. Thus the mechanism of cancer metabolism promotes the low expression of K+ in the Kv channel [24-26]. The partial suppression catabolic processes due to overload "Nodal point bifurcation anabolic and catabolic processes [NPBac]" and lack Acetyl-CoA in cancer tissue touches on Krebs Tricarboxylic Citric Acids cycle [TCA] via partial suppression mechanism transferring Oxaloacetates from cancer tissue TCA to cancer cells' TCA (Figure 4). The partial suppressed mechanism transferring Oxaloacetates from cancer tissue TCA to cancer cells' TCA violates link between cancer tissue TCA and both cancer cells' mitochondrial TCA and cancer cells' mitochondrial cytochrome system. Thus overload NPBac with partial suppressed mechanism transferring Oxaloacetates from cancer tissue TCA to cancer cells' TCA results in expression mechanism metastasis due to blocking oxidative destruction of synthesized high-molecular substances in cancer tissue (Figure 4). Also operations of cancer cells' cellular capacitors via related resonance waves promote movement cancer cells with the synthesized high-molecular substances within them to healthy tissue without overload "Nodal point bifurcation anabolic and catabolic processes [NPBac]" and lack of Acetyl-CoA and cause metastases. The use citric acids from citric juice, in which the enzymes for Citric Acids cycle are preserved, exerts expression Krebs tricarboxylic citric acids cycle (TCA) and increases Acetyl-CoA eliminating overload "Nodal point bifurcation anabolic and catabolic processes [NPBac]" and partial suppression catabolic anaerobic processes. Elimination overload NPBac with partial suppression catabolic anaerobic processes contributes to prevention additional metastasis in processes of up-to-date chemotherapy. Really excessive quantity of citric acids with appropriate enzymes increases quantity Acetyl-CoA due to mechanism maintenance stable index of Equilibrium Constant reaction in Krebs tricarboxilic acids cycle (1): Acetyl-CoA + Oxaloacetate ↔ Citric acid (Figures 3 and 4). This reaction in Krebs Tricarboxylic Acids Cycle [TCA] moves right saving stable Equilibrium Constant of the reaction Acetyl- CoA + Oxaloacetate → Citric acid. However this reaction moves left via increase Acetyl-CoA in condition increased quantity citric acid for saving stable Equilibrium Constant of the reaction Acetyl- CoA + Oxaloacetate ← Citric acid. Increased quantity of Acetyl- CoA eliminates overload "Nodal point bifurcation anabolic and catabolic processes [NPBac]" and partial suppression catabolic anaerobic processes that contributes to prevention additional metastasis in processes of up-to-date chemotherapy. Beside increased quantity citric acids exert Citric Acids cycle causing expression of catabolic anaerobic processes that stimulates also catabolic aerobic processes via mitochondrial frataxin protein operation with cytochrome c inhibiting cancer metabolism and preventing supplementary cancer metastasis in processes of upto- date chemotherapy. There are the clinical observations: I have treated the sick man whom was found the multiple metastases in visceral peritoneum. The sick man has refused himself from the offered alternative therapy of "Prolonged medical starvation during 45 days with small dosage cytotoxic remedy" [7-9,19] and has chosen up-to-date chemotherapy with Fluorouracil and Erbitux immunotherapy. Taking into account the above described mechanisms of the role citric acids in Citric acids cycle, I have recommended him to use citric juice from the squeezed two citrons by day which should be diluted in 1 litre water for prevention intestine irritation due to great concentration of citric acids. This method must be used simultaneously with chemotherapy as the supplementary method for prevention new metastasis. The patient has drunk the citric juice prepared in such mode during two months. Then patient has drunk the citric juice from the squeezed one citron daily which was diluted in 1 litre water. The weekly examinations showed that there were not found new metastasis by the patient during the period of two years. The state of the patient is satisfactory.

Acknowledgments
This article is dedicated to the memory of my daughter T.M. Ponisovska.
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Tables & Figures
Figure 1: The metabolism of a malignant tumor tissue and of a normal tissue
a) Nodal point of bifurcation anabolic and catabolic processes.
b) Huge anabolic processes with huge consumption of energy and Acetyl-CoA for anabolic processes leading to overloading "Nodal point of bifurcation anabolic and catabolic processes" [NPBac] leading to partial suppression of catabolic processes of oxidative phosphorilation suppression of catabolic processes of oxidative phosphorilation in cancer tissue.
c) Moderate metabolic processes displaying balance anabolic and catabolic processes in able-bodied tissue.
d) Alternative excretion of high-molecular substances within the structure rejected cells and the violation of excretion substances via oxidative processes due to partial suppression of catabolic processes of oxidative phosphorilation in cancer tissue.
e) Accumulation of energy into lactic acid for anabolic processes.
f) Normal excretion substances via catabolic processes of oxidative phosphorilation in able-bodied tissue.

Figure 2: Influences energy flow on interactions catabolic processes and anabolic processes in norm and in cancer pathology.
a) Balance catabolic aerobic exoergonic processes and catabolic anaerobic processes of oxidative phosphorilation due to mutual exchanges with moderate quantity energy (2nH+) in norm.
b) Balance catabolic anaerobic processes of oxidative phosphorilation and anabolic endoergonic processes due to mutual exchanges with moderate quantity energy (2nH+) in norm.
c) Inducing via moderate energy (+2nH+) of proliferative processes in nuclear anabolic endoergonic processes by ROS/H2O2/free radicals, produced by mitochondrial Cytochrom System in catabolic aerobic exoergonic processes in norm.
d) Disbalance between catabolic anaerobic processes of oxidative phosphorilation and anabolic endoergonic processes due to consumption huge quantity energy (+2000nH+) from catabolic anaerobic processes by anabolic endoergonic processes (the stricken off arrow [-2000nH+]) leading to partial suppression catabolic anaerobic processes in cancer metabolism.
e) The partial suppression of catabolic anaerobic processes causes disbalance between catabolic aerobic exoergonic processes and catabolic anaerobic processes of oxidative phosphorilation (+2nH+ and +1nH+ by the arrows between them) in cancer metabolism.
f) The great quantity ROS/H2O2/free radicals, produced by mitochondrial Cytochrom System in catabolic aerobic exoergonic processes, induce excessive irrepressible proliferative processes in nuclear anabolic endoergonic processes by excessive energy (+2000nH+) of free radicals in cancer metabolism.


Figure 3: Krebs Tricarboxylic Acids Cycle (TCA) in catabolic exoergonic process.
a) Transition catabolic anaerobic processes of oxidative phosphorilation from Glycolysis to Krebs tricarboxilic citric acids cycle.
b) Glycolysis' Product "Acetyl-CoA" is as "the nodal point of bifurcation anabolic and catabolic processes [NPBac]" as well as "the one part of the link joining Glycolysis with Krebs tricarboxilic citric acids cycle".
c) Oxaloacetate is as the closing link of circular Krebs tricarboxilic citric acids cycle as well as "the second part of the link joining Glycolysis with Krebs tricarboxilic citric acids cycle".
d) The joint between Acetyl-CoA and Oxaloacetate produces Citric acid as the primary link of driving mechanism Krebs tricarboxilic citric cycle which governs direction reaction among Glycolysis and Krebs tricarboxilic citric cycle.
e) The final Catabolic Products of Krebs tricarboxilic citric cycle are Carbon dioxide and Hydrogen ion.
f) Hydrogen ion is oxidized by Oxygen resulting in Water.


Figure 4: Interactions between anaerobic catabolic processes and aerobic catabolic processes via Krebs tricarboxylic acids cycles.
a) Oxaloacetates join three Krebs tricarboxilic citric cycles [mitochondrial TCA, cytoplasmic TCA and an organism's extracellular TCA] making circular pathways between these TCA cycles.
b) The final Products of all three Krebs tricarboxilic citric cycles [mitochondrial TCA, cytoplasmic TCA and an organism's extracellular TCA] are Carbon dioxide ions and Hydrogen ions.
c) The final Catabolic Products of Carbon dioxide ions are transferred to lung's alveoles by Carboxyhaemoglobin in blood of an organism where Carbon dioxide ions turn into Carbon dioxide.
d) Oxygen ions turn into Superoxide which reacts with Hydrogen ions resulting in Oxygen ion and Water in lung's alveoles.
e) The final Catabolic Products of Hydrogen ions react with Oxygen ion resulting Water due to Cytochrome C oxidase operation in mitochondrial Cytochrome C.

Figure 5: The targets of both the new methods cancer treatment and modern method of cancer treatment.
a) Balance catabolic aerobic exoergonic processes and catabolic anaerobic processes of oxidative phosphorilation due to mutual exchanges with moderate quantity energy (2nH+) in norm.
b) Balance catabolic anaerobic processes of oxidative phosphorilation and anabolic endoergonic processes due to mutual exchanges with moderate quantity energy (2nH+) in norm.
c) Inducing via moderate energy (+2nH+) of proliferative processes in nuclear anabolic endoergonic processes by ROS/H2O2/free radicals, produced by mitochondrial Cytochrom System in catabolic aerobic exoergonic processes in norm.
d) The main targets of modern method cytotoxic cancer therapy are directed to anabolic endoergonic processes in cancer metabolism (The arrow is directed to Anabolic endoergonic processes).
e) The main target of the new method cancer therapy is directed to disbalance between catabolic anaerobic processes of oxidative phosphorilation and anabolic endoergonic processes in cancer metabolism (the arrow is directed to the stricken off arrow [-2000nH+]).
f) Also the target of the new method cancer therapy is directed to disbalance between catabolic aerobic exoergonic processes and catabolic anaerobic processes of oxidative phosphorilation because of elimination disbalance between them making by elimination disbalance between catabolic anaerobic processes of oxidative phosphorilation and anabolic endoergonic processes in cancer metabolism (the arrow is directed to the arrow near [-1nH+]).
g) Also the target of the new method cancer therapy is directed to great quantity ROS/H2O2/free radicals which induce excessive irrepressible proliferative processes in nuclear anabolic endoergonic processes in cancer metabolism (the arrow is directed to the arrow near ROS/H2O2/free radicals).
h) Also the target of the new method cancer therapy is directed to Anabolic endoergonic processes due to elimination of great quantity ROS/H2O2/free radicals which induce excessive irrepressible proliferative processes in nuclear anabolic endoergonic processes in cancer metabolism (the arrow is directed to Anabolic endoergonic processes).

Figure 6: Partial Inhibition link between anaerobic catabolic processes and aerobic catabolic processes via Krebs tricarboxylic acids cycle in cancer metabolism.
a) Oxaloacetates join three Krebs tricarboxilic citric cycles [mitochondrial TCA, cytoplasmic TCA and an organism's extracellular TCA] making circular pathways between these TCA cycles.
b) Krebs Tricarboxylic Acids Cycle (TCA) in blood of an organism presents initial link between aerobic catabolic processes and anaerobic catabolic processes.
c) Krebs Tricarboxylic Acids Cycle (TCA) in cells' mitochondria presents final link between aerobic catabolic processes and anaerobic catabolic processes.
d) The treatment with great quantity of citric acid juice leads to partial Inhibition link between Krebs Tricarboxylic Acids Cycle (TCA) in blood of an organism and Krebs Tricarboxylic Acids Cycle (TCA) in cells' mitochondria.
e) Hence the treatment with great quantity of citric acid juice leads to partial Inhibition link between aerobic catabolic processes and anaerobic catabolic processes.
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