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The effect of alkalizing agents on malignant processes, from cytotoxic to genomic in cancer research.

Introduction

There will be described for the first time a mechanism for destroying cancer cells by intravenous injection of alkalizing agents, including sodium bicarbonate. This mechanism involves the well-known pathways of glycolysis, the utilization of sugars for producing the energy molecule ATP. Also described are certain characteristics of cancer cells that distinguish them from normal cells. The mechanism described exploits some of these differences between cancerous and normal cells.

There have been developed over the years many ways of treating cancer. One technique is the intravenous administration of alkalizing agents. Typical alkalizing agents that have been used for quite some time in cancer therapy include salts of the alkali metals. The alkali metals are those elements found in the left-hand column of the periodic table, including lithium, sodium, potassium, rubidium and cesium, in descending order. Commonly used salts of alkali metals include those of chloride, carbonate, bicarbonate, and others. As this column descends, salts of these elements become progressively more alkaline. Thus, cesium salts are preferred to those higher in the table (for example, sodium). Cancer has also been positively correlated with processes concerned with genes (genetic, familial). (1), (2), (3)

Alkali Metal Salts as Anticancer Agents

Certain salts of alkali metals have been used as infusions to combat human cancer. Examples include cesium chloride, cesium and rubidium carbonate, sodium carbonate, and sodium bicarbonate. (4) Although widely used, no mechanism for their actions as anticancer agents has been proposed.

Cancer Cells Utilize Less Oxygen

All animals and plants require oxygen for survival. Some bacteria and fungi do not; these anaerobic organisms developed before oxygen was present in the atmosphere. The oxygen requirement for cancer cells is lower than normal cells for a specific reason. The purpose of oxygen in metabolism is to provide an "electron sink," or place to dispose of an electron produced in the citric acid or tricarboxylic acid (TCA) cycle, generating the "energy molecule" ATP. Since this oxidative pathway has been turned off in cancer cells, the need to dispose of an electron is greatly reduced. (5), (6)

Since the TCA cycle has been turned off in cancer cells, the only ATP-generating pathway remaining in operation is the glycolytic pathway from sugar to pyruvate/lactate, producing a much smaller amount of ATP compared with that of the TCA cycle. This pathway results in an accumulation of lactic acid, thereby lowering the pH and creating another distinguishing characteristic of cancer cells. (6)

Lactic acid contains within its molecular structure only one carboxylic acid group (see Chart 5, pg. 94), and is described as a monocarboxylate. A specific protein found in the plasma or outer membrane of cells, known as a monocarboxylate transporter (MCT), is responsible for the transport of lactic acid from the cell (lactate excretion). It has been shown that the activity of the MCT found most prevalent in cancer (MCT4) is increased more than 3-fold by the hypoxic conditions found in cancer cells. (17) It is by this mechanism that cancer cells, known to generate excessive amounts of lactic acid (because of the fermentation mode) and which are also hypoxic (that is, have less oxygen), are capable of excreting large amounts of lactic acid.

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The cancer cell has put itself in a very precarious position. It has purposely and deliberately deactivated the major source of energy (ATP production by the TCA cycle) and has relied only on the glycolytic pathway, turning off the TCA cycle. If this pathway were to be blocked for any reason, the cancer cell has no other option than to undergo "programmed cell death," or apoptosis. As we shall see, cancer cells take this option when ATP production falls to a certain minimum (see Charts 1 and 2).

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The glycolytic pathway consists of a sequence of biochemical transformations in which sugar (typically glucose or fructose) is converted to a compound known as acetyl coenzyme A, or acetyl CoA, that enters the TCA cycle, resulting in the formation of a large amount of ATP. Only a small amount of ATP is generated by the glycolytic pathway. The first step in this process is the attachment of a phosphate group ([PO.sub.4.sup.-3]) to a sugar molecule (a process known as phosphorylation). (7) The enzyme performing this task in cancers is hexokinase II (HK II), which is elevated in cancer cells. The product, known as glucose 6-phosphate, is immediately transported across the outer membrane of mitochondria and is further processed within this organelle (see Chart 3). (8)

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In 1930, Otto Warburg, a German biochemist, proposed that the cause of cancer was an altered metabolism, from the utilization of oxygen in the generation of ATP to the anaerobic formation of lactic acid as a greatly reduced form of energy production. Whether this shift in metabolism is the cause of cancer or simply one result of it remains a controversy to this day. (9) During the 75-plus years since Warburg made this announcement, much additional information has been gained by researchers in elaborating on the exact biochemical mechanisms responsible for this transformation. Some of the details of these discoveries are presented below.

Voltage-Dependent Anion Channel (VDAC)

The most abundant protein in the outer mitochondrial membrane (OMM) is a pore known as the voltage-dependent anion channel, or VDAC (also known as porin). An anion is any negatively charged ion, including chloride ion, phosphate ion, glucose phosphate, and ATP. The VDAC can be in either an open or closed state (gated), regulating anions in entering or leaving mitochondria. Whether the VDAC is open or closed depends upon the voltage difference (net electrical charge) across the OMM. (10), (11) An extension of the protein chain forming the VDAC molecule is a peptide (a short length of protein) lying outside the mitochondrion. It is believed that this peptide regulates activity of the pore, allowing or blocking the transport of anions across the membrane. (12)

Hexokinase II is Bound to Mitochondria

The enzyme that attaches a phosphate group to glucose in cancer cells is hexokinase II (HK II), bound to the VDAC. An extension of the protein strand of HK II lies external to the enzyme and provides a means of attachment to mitochondria. Both this HK II peptide and the peptide extending from the VDAC contain among their residues some that bear charged groups. Examples of amino acids that carry charged groups are lysine (+ charged), arginine ( + charged), aspartic acid (- charged) and glutamic acid (- charged).

Proteins are by definition chains of amino acids having a specific sequence and linked by peptide bonds. An amino acid residue is that part of an amino acid that is not incorporated into the peptide bond or protein chain. The residue is what distinguishes one amino acid from another. This organic group is free to enter into various interactions with other chemical groups. Residues carrying charged groups in these two peptides (found in HK II and VDAC) allow for electrostatic, attractive bonds between them and the binding of HK II to the VDAC (see Chart 4).

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As indicated above, in cancer cells HK II attaches a phosphate group to sugars (phosphorylation) and is a required step for the transport of sugars into the mitochondria for further processing. HK II is also ATP-driven; that is, it requires the energy molecule ATP for its phosphorylating activity (as a car requires gasoline to run). As soon as the phosphorylated sugar forms, it immediately passes into the mitochondria through the VDAC. Once inside, it is processed by the glycolytic pathway with the generation of 2 ATP. This ATP passes out of the mitochondria also through the VDAC. On the surface of HK II is a cavity, or "active site," into which ATP binds. (11) It becomes obvious that it is to the advantage of the cell for HK II to be bound directly to mitochondria, not only for the purpose of injecting phosphorylated sugars directly into the mitochondria, but to also be able to immediately accept ATP directly from the mitochondria (see Chart 4).

Basic Amino Acids

To return to amino acid residues, there are only three types of amino acids: those that have acidic residues, those having basic residues, and those that are neutral. The acidic amino acids contain in their residues a carboxylic acid group, the basic amino acids contain at least one nitrogen atom, and the neutral amino acids have hydrocarbon residues (composed of only hydrogen and carbon) that may also include sulfur or nitrogen. When a basic amino acid is in an acidic medium (having a pH lower than 7 and containing the hydrogen ion [H.sup.+]), the nitrogen atom will bind [H.sup.+]. A nitrogen atom contains in its outer shell an unused pair of electrons capable of binding [H.sup.+] (a proton) that bind [H.sup.+] . This action conveys a positive charge to the amino acid residue carrying the nitrogen atom, shown as--[NH.sup.+] . As long as the medium remains acidic, the residue will carry a positive charge (see Chart 5).

If, for any reason, the medium becomes alkaline (pH greater than 7), the hydroxy ion ([OH.sup.-]) of the alkaline medium combines with the attached [H.sup.+] and forms water ([H.sub.2]O) from the combination of the bound [H.sup.+] and [OH.sup.-] of the medium, thereby destroying the positive charge on the amino acid residue (see Chart 6).

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Acidic Amino Acids

As indicated, an acidic amino acid is one that contains within its residue a carboxylic acid group symbolized by--C(O)OH (see Chart 5). The hydrogen atom (H) in this group detaches as [H.sup.+], leaving the remainder negatively charged. In alkaline medium containing sodium hydroxide, for example [Na.sup.+] [OH.sup.-], the hydroxide ion ([OH.sup.-]) combines with the [H.sup.+] ion detached from the amino acid residue, forming water ([H.sub.2]O), leaving the [Na.sup.+] ion as a replacement for the original [H.sup.+] ion. This reaction forms the sodium salt of the amino acid, but the acid remains negatively charged (see Chart 6). When an amino acid having an acidic residue is placed in an alkaline environment, the negatively charged residue remains unchanged.

Reactivity of Bicarbonate Ion

Bicarbonate ion, [HCO.sub.3.sup.-], is one component (negatively charged) of sodium bicarbonate. Only the bicarbonate ion is involved in chemical reactions of this compound; thus the sodium ion may be disregarded. When the bicarbonate ion reacts with any acid, represented by the symbol [H.sup.+], the bicarbonate ion decomposes with the formation of water and carbon dioxide, a gas. Since both water and carbon dioxide are neutral substances, carrying no electrical charges, the net result of reacting bicarbonate ion with an acid is the destruction of the acid and a resulting increase in pH (see Chart 9, p. 96).

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Some Basic Principles of Electrostatics

When a small object, for example metal or balsa wood, is insulated from the ground and electrically charged negatively, it has acquired an excess of electrons. When a similar insulated object is electrically charged positively, it is deficient in electrons. When two such objects are suspended by a thread in proximity, they will be attracted to each other if the charges are unlike (oppositely charged) or repelled if they have the same charge (either both positive or both negative). Put in simpler terms, like charges repel while unlike charges attract.

The attractive force between unlike charges is known as an electrostatic bond. An electrostatic bond requires the presence of both a positive charge and a negative charge. If either charge is separated from the other or is destroyed, the electrostatic bond is broken and the attractive force no longer exists. As we shall see, this principle is responsible for the detachment of HK II from the VDAC of the mitochondria in alkaline media.

Electrostatic Bonds Broken by an Alkaline State

An electrostatic bond is formed between unlike charges. As has been indicated, a positive charge on a basic amino acid residue (found in lysine, arginine, histidine) is destroyed in an alkaline medium. An electrostatic bond formed between the residue on any of these amino acids with acidic residues will be destroyed in an alkaline medium. Since HK II is electrostatically bound to the VDAC on the mitochondria, this bond will be broken in an alkaline medium resulting from the application of bicarbonate. The detachment of HK II from the mitochondria leads to the induction of apoptosis and cell death. (12), (15)

An alkaline medium is not the only cause of HK II detachment from the mitochondria. Certain antibiotics and other known substances can also cause HK II detachment, independent of a change in pH. All of these mechanisms lead to the induction of apoptosis and cell death (see Chart 10, pg. 96). (12), (15)

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Induction of an Alkaline State

There are two ways of inducing an alkaline state in a solution: the administration of an alkalizing substance and the destruction of the acidic component [H.sup.+]. (1), (2) Either of these actions will result in an increase in pH and an alkaline state. Most, if not all, biological solutions contain both acidic and basic substances. The destruction of the acid (only [H.sup.+], not the associated molecule) leads to an increase in pH arising from the alkaline substances normally present.

Blood is Buffered by Carbonate/Bicarbonate

A buffer is a combination of two substances, one acidic and the other basic. The purpose of a buffer is to maintain the pH of a solution at some chosen value. The normal body maintains a blood pH of approximately 7.4. When the pH is lowered (pH < 7.4), a condition of acidosis results and, conversely, when the blood pH is raised (pH > 7.4), a condition of alkalosis results. Both of these conditions may be treated successfully by administering an appropriate substance that modifies the blood pH.

A typical buffer consists of a mixture of an organic acid and the sodium salt of that acid in a specific proportion yielding a desired pH. The sodium ion of the salt raises the pH while the acidic component lowers the pH. When combined, the buffer acts to maintain a constant pH. The acidic component chemically reacts with an administered alkaline substance attempting to imbalance the pH by forming water. An administered acidic substance reacts with the alkaline component of the buffer by forming water, carbon dioxide, or other neutral, inert substances. Blood is buffered by a combination of sodium carbonate and sodium bicarbonate. Carbonate is the alkaline component, while bicarbonate is the acidic component.

Cancer Therapy with Bicarbonate Infusion

Because cancer cells are hypoxic, they generate most of their ATP by the glycolytic or fermentation pathway, not by an aerobic process (the citric acid cycle). The extensive generation of lactic acid by this pathway requires large amounts of lactate to be excreted from the cell to prevent cell death from an excessively low pH (acidic state). This problem for malignant cells is solved by the presence in the plasma membrane (that surrounding the cell) of an oversized pore. It is believed that it is through this large pore that the bicarbonate ion is preferentially admitted to cancer cells rather than normal cells. This difference between cancer cells and normal cells allows a selectivity in the admission of bicarbonate to cancer cells while excluding it from normal cells.

In a controlled demonstration in 2008 at the Ingles Hospital in Tijuana, Mexico of the safety of intravenous administration of sodium bicarbonate to a cancer patient, it was shown that 25 grams of bicarbonate infused over a 1-hour period had no effect on blood pH. (16)

Cancers are hypoxic for two reasons: the capillaries in cancers are formed by a process known as neogenesis (the generation of new blood vessels), resulting in capillaries that have a tortuous configuration or distorted path providing less oxygen to the cells; and the metabolic processes requiring oxygen (the TCA cycle) has been shut down by the cancer itself to avoid destruction by reactive oxygen species (ROS) generated by mitochondria functioning under hypoxic conditions. (1), (2)

Summary

Noncancerous cells rely on both the glycolytic (fermentation) pathway and the tricarboxylic acid (TCA, respiratory, or Krebs) pathway for ATP energy generation. Cancerous cells have almost totally inactivated the TCA (oxygen-requiring) cycle and rely almost entirely on the glycolytic pathway for energy (ATP) production. This transformation is tolerated because cancerous cells are acidic as well as hypoxic and require little oxygen for survival.

These differences are capitalized upon by alkaline therapy, the administration of substances that either (1) alkalize (raise the pH) of the cell or (2) destroy the acidic components of cellular fluid (cytoplasm). An example of the former technique is the administration of cesium chloride, while an example of the latter is the administration of sodium bicarbonate and ingestion of alkaline water.

The source of energy for all cells is the molecule ATP. In a normal cell, energy is generated by both the glycolytic and respiratory pathways. In cancerous cells, energy is generated almost entirely by the glycolytic pathway. The source of ATP production for both cell types is sugar, typically glucose. ATP is generated by the subcellular organelle known as the mitochondrion. Before sugar can enter the mitochondrion, it must undergo phosphorylation, the attachment of a phosphate group to the sugar. This operation is executed by the enzyme hexokinase II (HK II).

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HK II is bound to the mitochondrion by electrostatic bonds between a peptide (short-length protein) extending from HK II and a peptide extending from a mitochondrial membrane pore protein known as the voltage-dependent anion channel (VDAC). This channel in the outer mitochondrial membrane (OMM) serves two purposes for the cell: it transports phosphorylated glucose across the OMM into the mitochondrion and it transports ATP formed within the mitochondrion to the exterior. Since the phosphorylating enzyme HK II is bound to the transporting pore, HK II receives some of the ATP immediately upon release from the mitochondrion. This close proximity of HK II to the mitochondrion establishes a closely knit, cyclic relationship between phosphorylated glucose, ATP, HK II, and the mitochondrion.

The presence of alkalizing agents in the medium surrounding the mitochondrion breaks the electrostatic bonds between HK II and the mitochondrion, disrupting the immediate receipt of ATP and the ability of HK II to phosphorylate glucose (an absolute requirement for glucose transport)

Cancerous cells have an absolute dependency upon the ATP generated by the glycolytic pathway within the mitochondrion for their energy requirement. The disruption of this critical source of energy leads to the induction of apoptosis (programmed cell death) for cancerous cells. Other substances, unrelated to changes in pH, can also dislodge HK II from mitochondria, leading to the induction of apoptosis and cell death. (15)

[c] 2009 BRI

References

(1.) Bradford RW, Allen HW. The primordial thesis of cancer. 1991. Bradford Research Institute (BRI). Report No. 30.

(2.) Bradford RW, Allen HW. The primordial thesis of cancer. Med Hypotheses. 1992;37;20-23.

(3.) Bradford RW, Allen HW. Butyric acid therapy as a new adjunctive in the treatment of degenerative diseases. BRI Report No. 2. 1986.

(4.) Brewer, AK. The high pH therapy for cancer tests on mice and humans. Pharmacol Biochem Behav. 1984;21(suppl 1):1-5.

(5.) Wikipedia [Internet]. Citric Acid Cycle, http://en.wikipedia.org/wiki/Citric_acid_cycle.

(6.) Smallbone K, Gavaghan DJ, Gatenby RA et al. The role of acidity in solid tumour growth and invasion. J Theor Biol. 2005;235:476-484.

(7.) Davis R. Summary: glycolysis and the citric acid cycle [Internet lecture outline]. Principles of Cell and Molecular Biology; San Diego State University. http://www.sci.sdsu.edu/class/bio202/TFrey/Glycolysis_TCA.html.

(8.) Wikipedia [Internet]. Hexokinase. http://en.wikipedia.org/wiki/Hexokinase.

(9.) Garber K. Energy boost: the Warburg effect returns in a new theory of cancer. J Natl Can Inst. 2004;96:1805-1806.

(10.) Wikipedia [Internet]. Porin (protein). http://en.wikipedia.org/wiki/Porin_(protein).

(11.) Abu-Hamad S, Zaid H, Israelson A et al. Hexokinase-I protection against apoptotic cell death is mediated via interaction with the voltage-dependent anion channel-1: mapping the site of binding. J Biol Chem. 2008;283:13482-13490.

(12.) Pastorino JG, Shulga N, Hoek JB. Mitochondrial binding of hexokinase II Inhibits Bax-induced cytochrome C release and apoptosis. J Biol Chem. 2002;277:7610-7618.

(13.) Pastorino JG, Hoek JB. Regulation of hexokinase binding to VDAC. J Bioenerg Biomembr. 2008;40:171-182.

(14.) Rostovtseva TK, Bezrukov M. ATP transport through a single mitochondrial channel, VDAC, studied by current fluctuation analysis. Biophys J. 1998;74:2365-2373.

(15.) Goldin N, Arzoine L, Heyfets A et al. Methyl jasmonate binds to and detaches mitochondria-bound hexokinase. Oncogene. 2008;27:4636-4643.

(16.) Garcia A. Ingles Hospital; Tijuana, Mexico. Personal communication. October 2008.

(17.) Ullah MS, Davies AJ, Halestrap AP. The plasma membrane transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1(alpha)-dependent mechanism. J Biol Chem. 2006;281:9030-9037.

by Prof. Robert W. Bradford

Bradford Research Institute 858 3rd Ave. #150 Chula Vista, California 91911 RWBMC@hotmail.com
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Date:Aug 1, 2009
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