In my previous articles on cancer, I did not discuss the role of acids, bases and antioxidants in detail. But with the current hype about the miraculous nature of basic water, antioxidant foods and drugs, I feel compelled to step in and set the records straight with currently available medical literature.
The efficacy of acids, bases and antioxidants in cancer therapy is not a myth. It has biochemical basis informed by modern research (SS Kim et al, 2004; Ian F. Robey & Lance A. Nesbit, 2013). The apparent controversy surrounding this subject emanates from poor coordination of research findings.
I have read articles (Bradley A. Web et al, 2011; Shi Q. et al, 2001; Silver M. et al, PubMed 2011) supporting systemic alkalosis or systemic hyperacidosis as the dominant toxic factor in cancer development. I have also watched video presentations claiming that cancer development is just a natural cellular adaptation to toxic environment, which is corrected by normalizing the environment.
These claims are to say the least, unbalanced truths. By the end of this discussion it would have become obvious that there is no basis for undue generalizations in the management of cancer. There still remains the need for expert judgement in formulating a cancer treatment protocol.
First, let me state that the human body will literally rust away like a nail left under the rain over time without inbuilt natural protective mechanisms. To prevent rust or oxidation, most macromolecules essential for human existence are shielded from molecular oxygen or oxygen equivalents with hydrogen molecules (reduction). Oxygen equivalents are those compounds that remove these protective hydrogen molecules from other compounds.
They are also called oxidizing agents. Compounds that restore these hydrogen molecules are called reducing agents. The two most important organic reducing agents in human body are glutathione and ubiquinone, while the two most important oxidizing agents are molecular oxygen and free oxygen radicals.
APOPTOSIS AND GROWTH SUPPRESSOR GENES
The human body cells are normally continuously moving from resting phase, to growth phase and then multiplication phase. This continuous state of growth and multiplication means that any organ can potentially grow to any size, depending on its natural growth rate. By inference all human beings may also grow into giants. It even suggests immortality of human beings.
Thankfully, every cell has an inbuilt apoptotic clock that ensures that it dies after a specified number of days, making room for incoming cells. Thus red blood cells, for instance, are recycled every 120 days. The size and shape of the cells of individual organs are equally limited prior to their date of apoptosis, by growth suppressor genes (notably p53, AP1, NF-kB) located in the nucleus.
Anything that hinders the functions of apoptosis and growth suppressor genes would obviously be expected to unleash uncontrolled growth and multiplication of cells in any organ of the body. This rapid growth of disorganized and poorly differentiated cells is called cancer.
All anti-growth suppression and anti-apoptosis agents are called carcinogens. They may be chemicals, radiations, biochemical molecules, acids, bases, free radicals, heat, cold, etc. But they all exert their effect by in activating apoptosis gene or growth suppressor gene. They accomplish this by corrupting the gene coding system in such a way that the codes are wrong (missense) or mean nothing (nonsense).
The code is corrupted due to the insertion of the wrong amino acid code into a gene sequence or the excision of the right amino acid code from the sequence. Consequently the t-RNA misreads or miss-senses the expression of the right apoptosis or growth suppressor protein.
TOXINS, FREE RADICALS AND CARCINOGENS
Toxins are basically those compounds whose activities will directly or indirectly lead to human rust and death by causing catabolic or destructive oxidative reactions in body tissues. The high powered toxic tissue oxidizing agents are called free radicals (ROS and RNS), which are basically free ionized oxygen or Nitrogen atoms (O2- and N2- )
When a toxin causes a gene altering damage in the nuclear region of a cell (oxidative nuclear damage) it is then known as a carcinogen. As such not all toxins are carcinogen. Aflatoxin (from mold) is not only toxic to liver cells, but ultimately causes liver cancer, making it a carcinogen.
The detoxification process mainly converts lipid soluble toxins into excretable water soluble glucuronides in three steps. In step one the toxins are aggregated and isolated in the specific organs that neutralize them.
Then glucuronic acid is attached to them in the presence of glutathione which the protective hydrogen molecules. (Note that in fighting oxidants hydrogen (non-ionized) carried by reduced NADPH is a friend, while in acid-base balance ionized hydrogen is the enemy).
Free radicals can also contribute to cancer development by inducing genetic mutation through oxidative nuclear damage, or suppress cancer growth by promoting apoptosis. Step three is the excretion of the toxins.
Compounds use to replenish hydrogen molecules in glutathione and other endogenous reductase enzymes are called antioxidants. A lot of these reducing agents occur naturally in fruits and vegetables. Others are available as drug extracts from plants and animals.
Individual antioxidants target different steps of the detox process. This is why balanced nutrition by itself goes a long way to keep our bodies toxin free. The air we breathe, the food we eat, the water we drink, and the environments we live in are all full of toxins, including heavy metals. To survive as human beings, an extensive detoxification mechanism has to exist.
Every body tissue has detox ability, but the liver, gut, and lymphoid tissues and kidneys play the dominant role. Thus most toxins are trapped, neutralized and excreted through feces, urine or bile. Stagnation or obstruction of flow in any of these three organs, generally leads to a toxic state.
Stressors and nutritional insufficiencies that weaken the immune system also contribute to toxic states allowing micro-organisms to multiply and generate additional toxic substances that must be removed.
Successful detoxification requires a lot of energy, which comes from glucose metabolism. Biochemical energy is not measured in Joules, but in ATPs (Adenosine Triphosphate). The metabolic process for converting glucose to ATP is called glycolsis.
During aerobic glycolysis one molecule of glucose combines with two molecules of ADP3- (Adenosine Diphosphate) and two ionic phosphoric acid molecules to yield two ionic ATP4- molecules and two lactate molecules. The ionic ATP4- molecule gives up one Hydrogen proton (H+) to yield one molecule of ionic ADP3-, which is reused in glycolysis.
Under anaerobic (low oxygen) conditions, ATP is generated differently. One molecule, each, of ADP3- and ionic phosphoric acid accumulated from aerobic glycolysis recombine without glucose to form one molecule of ATP4+ and one hydroxyl molecule. Two hydrogen protons combine with two bicarbonates to end up as carbonic acid inside body cells.
Glycolsis can be aerobic when it consumes molecular oxygen, or anaerobic when it consumes oxidizing agents. Both the detox reactions and glycolsis are driven or catalyzed by enzymes, which depend on the availability of specific micro-molecules, proteins, amino acids and vitamins as cofactors for their functions.
By the time enough ATP is generated to keep the body toxin safe, enough carbonic acid hydration of respiratory carbon dioxide (CO2) has accumulated to keep the inside of every cell perpetually acidic. In a highly toxic state, which includes rapid proliferation of cells, this intracellular acid builds up exponentially beyond survivable limits.
Cancer cells are known to rapidly outgrow their blood supplies and go into severe hypoxic states. This is why the cancer cell nucleus has to rapidly increase the expression of sodium driven proton extruding proteins and enzyme proteins through nuclear sensing of sharp rise in HIF.
Thus, by default, the Intracellular fluid (ECF) of every cell is acidic (low pH) while that of the extracellular fluid (ECF) is alkaline (high pH). It is important to note at this point that while intracellular fluids exist in compartments inside the cells, extracellular fluids coalesce to form a pool in which all body cells submerged.
This ECF pool is represented by intercellular fluid, lymph, blood, and glandular secretions, all of which feed into the circulatory system of the body. ECF acid or base build up in any part of the body is ultimately dissipated into the circulatory system, which centrally maintains a mildly basic pH of 7.20 -7.40.
In addition to mobilizing ammonium and bicarbonate ions the central buffer system has the ability to move chloride ions in and out cells (chloride shift) to maintain acid-base balance.
MEMBRANE SENSORS AND TRANSPORTERS
To keep intracellular acidity below lethal level, the inner surface of the cell membrane has acid sensors and transporters that detect abnormal rise in intracellular acidity and trigger increased extrusion of hydrogen and retention of alkaline bicarbonate ions.
This trigger is mediated by the rise in the blood level of hypoxia induced factors (HIF) and probably acidosis induced factors (AIF). On detecting this rise in HIF, the nucleus temporarily increases the expression of Na-driven proton transport proteins and histidine rich basic proteins.
The ammonium radicals on the amino acids of these basic proteins (especially histidine) serve as physiologic buffers for organic acids.
“Protonation and de-protonation has been experimentally shown to change protein structure and thus, alter protein-protein binding affinity, change protein stability, modify protein function, and alter subcellular localization (Schonichen et al., 2013b).
Evolutionarily, histidines must confer some selective advantage for cancers, as 15% of the 2000 identified somatic mutations in cancer involve histidine substitutions, with Arg-to-His being the most frequent (Kan et al., 2010)”.
The nucleus also temporarily steps up the expression of important enzyme proteins that catalyze the buffer reactions, namely mono-carboxylate, carbonic anhydrase, and aminotransferase enzymes.
In a similar manner the external surface of the cell also has alkaline sensors made up of G-protein coupled surface receptors, which also communicate with the nucleus to increase or decrease the expression of relevant proteins and enzymes. As tissue hypoxia decreases, the level of HIF decreases along with nuclear expression of proton extrusion proteins and enzymes.
Failure of this return to normalcy has been observed as one of the hallmarks of early cancer. What started out as a normal adaptive change becomes persistent because of irreversible genetic modifications that triggered it.
CELLULAR SURFACE ACID/BASE REVERSAL
The central physiological buffer system has a maximum capacity to neutralize up to 30 micromoles of acid/gram tissue/min in systemic acidosis or 5-10 micromoles of base in alkalosis.
Beyond these levels, normal body cells are unable to continue their buffer functions because the enzymes are deactivated. At this point there is a reversal of the normal acid-base distribution on either side of the cell membrane, which is lethal to normal issues. In some critical situations, chloride ions are shifted massively into all body cells (chloride shift) to urgently dilute the extracellular acidity.
But the gastric cells have the natural ability to survive in the presence of high extracellular acidity (HCl at pH of 6.6). How they manage this high extracellular acidity then becomes very important in understanding how cancer cells survive high extracellular acidity with normal intracellular acidity for their survival and proliferation. Some cancer cells are known to have accumulated genetic adaptations that enable them to survive extreme pH conditions (carbonic acid at pH of 6.6).
Gastric cells are shielded from concentrated HCl secreted into the stomach mainly by structural barriers (thick basement membrane, thick mucosal layer and thick mucous layer). There are no natural inhibitors of hydrogen potassium ATPase enzyme that catalyzes the final phase of acid excretion.
In severe cases of Peptic Ulcer Disease (PUD), Gastro-esophageal reflux (GERD), or Zollinger-Ellison Syndrome, when this natural barrier is ulcerated by concentrated HCl, some gastric lining cells undergo goblet intestinal metaplasia (transformation into ectopic intestinal epithelium in the stomach) to secrete neutralizing alkaline fluids into the stomach.
While there is no natural attempt to control the hydrogen potassium ATPase enzymes, pharmacological intervention with proton pump inhibitors (PPIs) like omeprazole has been successful in reducing gastric secretion in severe cases of chronic gastric hyperacidity.
Similarly some esophageal epithelial cells undergo gastric metaplasia to become gastric cells in the face of chronic exposure to reflux gastric acid (Barrett’s Esophagus). Acquisition of this missing ability to control hydrogen potassium ATPase and sodium driven proton extrusion by monocarboxylate enzyme appear to be critical to the survival of cancer cells
IN EARLY CANCER
It is important to note that the natural response to extracellular hyperacidity in the GIT depends on the stage and localization of the acidity. Both goblet metaplasia and gastric metaplasia have been recognized as precancerous lesions (carcinoma in situs). At the early stage of Barret esophagus, the response is only structural to prevent cell wall damage.
But when the barrier has failed in the stomach, the response is alkaline secretion. A person on preventive alkaline water will be helping to neutralize the added hypoxic acidity of early cancer in Barret’s Esophagus and chronic PUD, but not in any way preventing the occurrence of cancer itself, since proton extrusion in cancer is irreversible.
Any cancer caught at the in situ stage is usually best treated with surgical excision and radiotherapy, rather than alkaline water.The question then is: “Why did prophylactic alkaline water not prevent the metaplasia?”
The answer to that is that while oral alkali intake may cap out at micromoles of alkali per gram tissue, cancer proton extrusion acid build up ranges in nanomoles per gram tissue (a thousand times more). Also intracellular hypoxia and hyperacidity are not the only risk factors for cancer.
Radiations are known to be commonly responsible for skin cancers, even as HPV is known to be responsible for cervical cancer. Prophylactic alkalosis has not been reported to prevent any of them. Sticking to the hype that alkaline water is the best way to prevent and even cure cancer, puts people at risk of missing early opportunities to truly cure cancer.
Alkaline water intake will help the body maximize the physiological adaptive response acidosis. Unfortunately, even at maximum physiological capacity, extracellular buffers are no match for cancer intracellular proton extruders.
As the well adapted cancer cells grow and multiply freely their neighboring non-cancerous cells are rapidly destroyed by ECF hyperacidity creating more space for them to occupy. Thus cancer invasiveness has been shown to correlate with the degree of acid-base reversal across the cancer cell membrane.
At the advanced stage of cancer with ECF acidity readings in nanomols compared to orally boosted alkalinity readings in micromoles, buffer therapy has been shown to be resisted by cancer cells. One such reported example is the inefficacy of a basic drug doxorubicin used in the treatment of Leukemias and lymphomas.
Going by what has been discussed so far, it is obvious that externally sourced acids and alkali cannot be safely loaded to outweigh tumor generated levels in ECF and ICF. It is also understandable that no single pH balancing agent, can be used to treat both acid sensing and alkaline sensing cancers.
Preventive or prophylactic intake of acidic or alkaline liquids or foods remain relevant only within the physiological buffering range, when adaptive changes are still reversible. Unfortunately at that point the tumor generated acidity would have risen to resistant levels. Preventive alkaline water intake in a person with undiagnosed acid sensing cancer is not likely to retard the growth of the tumor.
Similarly preventive intake of alkaline water in a patient with undiagnosed alkaline sensing cancer will encourage it to grow and establish faster. Patients receiving treatment for emesis gravid arum (vomiting in pregnancy) for instance, cannot be on preventive alkaline regimens in the face of systemic alkalosis from heavy loss of gastric acid through vomiting.
However, it is possible that some people are unable to fully optimize the natural buffer system, due to genetic predisposition or problems related to amino acid metabolism. In such situations, preventive acid or base intake supplements the patients effort to achieve maximum physiological buffering. This can easily account for some of the spectacular results observed in some patients whose cancers were caught early.
In conclusion, the management of cancer remains complicated. When there is a strong family history or occupational predisposition for cancer, cancer screening needs to be done early to search for risk factors and genetic markers.
Where there are suggestions of cancer predisposition, full blood tests, scans, biopsies, endocrinological tests, and radiological test should be done by a primary care provider and reviewed by a team of experts in radiology, hematology, pathology, oncology surgical oncology, gastroenterology, and international medicine.
Ian F. Robey and Lance A. Nesbit, Investigating Mechanisms of Alkalinization for Reducing Primary Breast Tumor Invasion
Bradley A. Webb, Michael Chimenti, Matthew P. Jacobson & Diane L. Barber, Dysregulated pH: a perfect storm for cancer progression
Silvia M. Titan1, Otávio C.E. Gebara2, Silvia H.V. Callas2, Ana O. Hoff3, Paulo M. Hoff2 and P.C.A. Galvão2, Case report: a rare cause of metabolic alkalosis, 2011
SS Kim, HW Yang, HG Kang, HH Lee, HC Lee, DS Ko… – Fertility and sterility, Quantitative assessment of ischemic tissue damage in ovarian cortical tissue with or without antioxidant (ascorbic acid) treatment, 2004 – Elsevier
M Valko, CJ Rhodes, J Moncol, MM Izakovic… – Chemico-biological… , Free radicals, metals and antioxidants in oxidative stress-induced cancer, 2006 – Elsevier
Rofstad EK, Mathiesen B, Kindem K, Galappathi K. Acidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude mice. Cancer Res. 2006;66(13):6699-6707. doi: 10.1158/0008-5472.CAN-06-0983.
Gillies R. J. (2002). In vivo molecular imaging. J. Cell Biochem. Suppl. 39, 231-238 10.1002/jcb.10450 (monocarboxylate transporters and Na-driven proton extrusion)
Shi Q, Le X, Wang B, Abbruzzese JL, Xiong Q, He Y, Xie K. Regulation of vascular endothelial growth factor expression by acidosis in human cancer cells. Oncogene. 2001;20(28):3751-3756. doi: 10.1038/sj.onc.1204500.
Gallagher F. A., Kettunen M. I., Day S. E., Hu D. E., Ardenkjaer-Larsen J. H., Zandt R., et al. (2008). Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate. Nature 45
Gatenby R. A., Gillies R. J. (2004). Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer 4, 891-899 10.1038/nrc1478 (Pasteur Effect)