Cancer Metastasis Rev. 2014 Dec;33(4):1095-108. doi: 10.1007/s10555-014-9531-3.
Microenvironmental acidosis in carcinogenesis and metastases: new strategies in prevention and therapy.
Fais S 1, Venturi G, Gatenby B.
- 1Department of Therapeutic Research and Medicines Evaluation, Unit of Antitumor Drugs, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, Italy, firstname.lastname@example.org.
Much effort is currently devoted to developing patient-specific cancer therapy based on molecular characterization of tumors. In particular, this approach seeks to identify driver mutations that can be blocked through small molecular inhibitors. However, this approach is limited by extensive intratumoral genetic heterogeneity, and, not surprisingly, even dramatic initial responses are typically of limited duration as resistant tumor clones rapidly emerge and proliferate. We propose an alternative approach based on observations that while tumor evolution produces genetic divergence, it is also associated with striking phenotypic convergence that loosely correspond to the well-known cancer “hallmarks”. These convergent properties can be described as driver phenotypes and may be more consistently and robustly expressed than genetic targets. To this purpose, it is necessary to identify strategies that are critical for cancer progression and metastases, and it is likely that these driver phenotypes will be closely related to cancer “hallmarks”. It appears that an antiacidic approach, by targetting a driver phenotype in tumors, may be thought as a future strategy against tumors in either preventing the occurrence of cancer or treating tumor patients with multiple aims, including the improvement of efficacy of existing therapies, possibly reducing their systemic side effects, and controlling tumor growth, progression, and metastasis. This may be achieved with existing molecules such as proton pump inhibitors (PPIs) and buffers such as sodium bicarbonate, citrate, or TRIS.
To learn more about the prevention and non-invasive treatment for Cancer read the following introduction to the pH Miracle for Cancer by Dr. Robert O. Young:
The pH Miracle for Cancer is coming out next week. I thought you might enjoy a preview by reading the introduction – I am very, very grateful to be able to share with you my cancer research I call the New Biology(R). I also refer to my research as the pH Miracle – a new way of living, a new way of eating, a new way of thinking. Some of the questions I will be covering in the pH Miracle for Cancer include:
What is Cancer?
What is the cause of all cancers? (Is cancer a mutant cell, a virus, a mold? Or is cancer an acidic liquid?) Is cancer a noun or is it actually an adjective that explains what’s happening to the body cells? Are tumors bad or good? What role does the lymphatic system play in preventing and reversing a cancerous condition? The focus for preventing and reversing cancer must be on the alkaline pH of the body fluids as a systemic acidic condition. The key to preventing and/or reversing cancer is to obtain the necessary sustainable energy for optimal body function and the elimination of toxic acidic waste products from diet, metabolism, respiration and the environment that all contribute to the cause of a cancerous condition.
Most of the last 30 years of my cancer research has been focused on what is happening to the cells as it pertains specifically to the environment around those cells. I love this quote by Ralph Waldo Emerson: “What lies behind us and what lies before us are tiny matters compared to what lies within us.” The focus of my cancer research has been specifically on what lies within us and, more specifically, how the internal fluids of the body affect the health, energy, and vitality of the human cell, tissues, organs and glands. Dr Benjamin Rush, eminent physician and signer of the Declaration of Independence, said: “Unless we put medical freedom into the Constitution, the time will come when medicine will organize into an underground dictatorship. To restrict the art of healing to one class of men and deny equal privileges to others will constitute the Bastille of medical science. All such laws are un-American and despotic.”
As I think about my vision, the relative purpose of medicine I believe medicine must include not just the treatment but also the prevention of illness and the promotion of health and fitness, rather than just focusing all of our attention on a specific diagnosis or even the treatment of the disease. Because disease is an illusion! In reality, disease is the body trying to prevent over-acidification or fermentation or breakdown of the body cells, tissues, organs or glands.
Disease is the body in preservation mode trying to maintain the homeostasis of the internal fluids of the body, which are all alkaline.
I believe that the ultimate purpose of medicine is to help people discover something fundamental within themselves. And that is an awareness of the true source of wellbeing, the true source of joy, the true source of contentment that we all seek which lies in one’s mind and in one’s heart – which are the emotions and the spirit. And this is important so that you and I can all begin to be free from the process of grasping for happiness in a physical world.
To support this approach, this theory, I believe we must begin to embrace a more spiritual vision of ourselves and of humanity as a whole, while at the right time providing great love, care, and attention to the physical body. Then, and only then, will medicine (or the treatments that medicine is current performing) help people discover this non-physical, spiritual dimension of themselves. And when this happens I believe that we can live and work with less fear.
Rather than working in fear you can work in its opposite – you can work in faith. You are going to have less stress grasping to preserve the physical body at all costs, then I believe you can truly be happy, energetic, and free from ALL sickness and disease, especially cancer.
Several years ago Shelley and I had the opportunity to have a wonderful experience with Dr. Lawrence Carter who is the caretaker of the estate of Martin Luther King, at Morehouse College and also the protégé of M. L. King, and there he honored. The most important thing that I learned about Dr. Carter was his openness to not just thinking outside the box, because we talk a lot about thinking outside the box, but making our box of knowledge bigger. I would like to suggest rather than thinking outside the box as you contemplate my theories on the prevention and treatment of cancer but making your box bigger to include all truth. I would also suggest as you read this book that you do not have to think outside the box, you just need to make your box of knowledge bigger to allow for new technology, new biology, and new protocols that are effectively making the difference, specifically in the prevention and treatment of cancer.
I truly believe in the words of Gandhi when he said, “you must be the change you want to see.”
If you are looking for the cure for cancer, I believe you must be change you want to see. You’ll have to look at cancer differently, not outside the box but inside the box making it bigger. Expanding your views and your perspective as it relates to prevention and the true cause of cancer.
Now, before you start exploring the pH Miracle for Cancer, I must start by defining a ‘pH miracle’. I would suggest that a ‘pH miracle’ is a natural phenomenon, that is not currently understood by medical researchers, specifically in the cause and effect relationship. What is the cause? Is cancer a cause for disease? I say NO! Cancer is the body perfectly attempting to maintain alkaline homeostasis. Cancer is the body in perfect preservation mode trying to maintain its natural healthy alkaline design. So first, you must understand that cancer is unequivocally not a disease, but a symptom or better yet an effect of gastrointestinal, respiratory, environmental and metabolic acids that build up in the blood and then thrown off into the tissues poisoning and suppressing our immune system making it increasingly difficult to maintain the alkaline pH of the internal fluids of the body. Metabolic, respiratory, environmental and dietary acids also destroy the white cells’ ability to remove toxins and the cells which they spoil or degenerate.
What I’m simply suggesting is that cancer is not a cell, but an acidic toxic liquid that spoils and degenerated the body cells that make up our tissues, organs and glands. This happens when toxic acidic waste products are not properly eliminated through the four channels of elimination, which are urination, perspiration, respiration and defecation.
Let’s now look at the current medical definition of cancer. What is it? Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal body cells. If the spread is not controlled it can result in death. Cancer is caused by both external factors, some of which are known and are common in our society such as tobacco, chemicals, radiation (from our cellular phones) and internal factors: hormone imbalances, immune deficiency and gene mutations – which is what they’re suggesting. These factors may act together in a sequence to promote what is called carcinogenesis. This is the classical definition of cancer, taken directly from the American Cancer Society.
What is being suggested by current medical science is that the cancer is some mutating cell – a transmutation of the genes – triggered by internal or external factors. This is true but what is not understood is these internal or external factors are the acidic waste products of diet, metabolism, respiration and the environment. When you are dealing with any symptom or an effect, you need to look at the cause. Whether externally or internally, the focus traditionally has been to look at the matter or cells that make up your tissues, organs and glands rather than looking at the internal environment around the matter. And, to understand the cause of cancer is very simple just like the treatment. The New Biology® explains the cause and effect of all sickness and disease and specifically cancer as well as how to improve the quality and quantity of life without chemical therapy, radiation or surgery. The pH Miracle for Cancer is a drug-free protocol to a cure for cancer!
Let me give you an example. Enervation (ie, lack of energy), muscle weakness, you’ve probably seen the commercials on television, it’s a new disease they call restless legs syndrome (RLS) for which there are drugs that supposedly treat the syndrome. Current medical researchers want to put everything in a disease modality – a nice little box – that has a specific treatment. Yet restless legs syndrome is weakness or loss of electrical power to the muscles. It’s not a disease. But, by causing a flagging of the toxic elimination from the tissue, the blood becomes charged with these metabolic toxic acids and when it’s charged with these metabolic toxic acids the blood has to purify itself by throwing these metabolic toxic acids into the tissues to maintain its delicate pH balance of 7.365. This is what I call the body in preservation mode, which leads to what I refer to as latent tissue acidosis or acid build-up in the connective and fatty tissues. Acid is poison in the blood, and if that poison is not eliminated through urination, defecation, respiration or perspiration the body has to purify itself so it eliminates this acidic poison into the connective and fatty tissues. This is the disease, or is it? Not even skin challenges when the acids accumulate beyond the toleration point, a crisis takes place, which means that the acidic poison is being eliminated through the pores of the skin.
Looking at the 2012 statistics for cancer, this coming year in America we’re looking at 1,400,000 new cases of cancer. By the way, this statistic doesn’t even include skin cancer, which is actually bigger than lung cancer, breast cancer or prostate cancer combined. And, prostate cancer is known to be the leading cause of death in men while lung cancer being the leading cause of death in women. And yet when we look at cancer, the new incidents of cancer and the new diagnoses are skin cancers because the skin is the third kidney – the largest acid elimination organ for removing acidic toxic waste products. And if acids are not properly eliminated through normal elimination channels, then those acids are thrown out into the tissues and this is what’s not currently recognized or understood by medical science.
This is the way the blood maintains its delicate alkaline pH and purity by either eliminating acid through urination or defecation or throwing it into the connective or fatty tissues which leads to this crisis, this poisoning, this elimination through the pores of the skin, again the third kidney! And this is not a disease! The only disease is systemic, because acids flow out through your whole body. They are the waste products of metabolism, diet, respiration and the external toxic environment.
Your body is like a car. You are constantly on 24/7 and you require energy and when energy is being used, a waste product like carbon dioxide or carbon monoxide or lactic acid or uric acid is being created. So acid is constantly being created by the body cells, which has to be eliminated or it will cause cancer!
When energy is being used to think, to move, to breathe, at the same time an acidic waste product is being created and this acidic waste product needs to be eliminated. If the acid is not eliminated, it is pushed out into the connective tissue. It is your connective tissue that becomes the ‘acid catcher’ in order to maintain the purity and alkalinity of the blood. The blood has to maintain its purity and alkalinity and this is why the blood has a constant pH of 7.365. If it varies even just one-tenth of one point you can have ill effects. The proper healthy pH balance of the blood is 7.365. If the blood pH starts dropping or if it starts going up, the body will do whatever it can to maintain its delicate pH. This is very significant in order to understand the cause and treatment of cancer and why it’s not a cell but the spoiling of the cells by dietary and/or metabolic acids, which have not been properly eliminated through normal elimination. When you are enervated or fatigued you do not have the energy to move the acidic waste products out of the body to maintain the purity of the blood. When this happens the blood pushes these acidic waste products out into the connective and fatty tissues.
For example, when acidic waste elimination takes place through the mucus membrane of the nose, it is called a cold – catarrh of the nose. And when this crisis is repeated for years the mucus membrane thickens and ulcerates, and the bones enlarge, closing the passages. At this stage hay fever, then asthma develops. When the tonsils or any other respiratory passages become the seat of the crisis of acidity (because the acids were not properly eliminated through urination or defecation or respiration or perspiration) then we have tonsillitis, laryngitis, bronchitis, asthma, pneumonia, and finally cancer. You see, it’s progressive. It’s the same disease at different levels of acidity. All of these symptoms are happening in different progressions from the same thing – just different levels of states of acidosis.
When acid is located in the cranial cavity we have dementia, Alzheimer’s, Parkinson’s, muddle thinking, and/or forgetfulness. If the acids accumulate in the digestive area, we end up with irritable bowel syndrome, gastro intestinal problems, stenosis, and colitis. And, when the acids locate in the pelvic tissue, or in the breasts, we end up with micro-calcifications and finally cancerous breast and reproductive organs. When the body is in the preservation mode, it is using alkaline buffers such as calcium, potassium, magnesium and sodium to neutralize or solidify the acidic liquid waste.
This is why I first see, using Ultrasound imaging, micro-calcifications in the pelvic area and in the breast tissue prior to the cancerous breast condition. The buffering of toxic acidic waste, forming micro-calcifications always precedes the cancerous condition of the tissue, organ or gland. Even in prostate cancer.
Hence all cancerous conditions are the expulsion of acids from the blood and then the tissues, organs and glands at different points and are essentially the same character evolving from the same cause, namely systemic acidosis – a crisis of toxemia. The description can be extended to every organ of the body: the lung, the liver, the pancreas, the bowels, the brain, including the largest organs which have the highest incidents, the skin. Any organ that is enervated or fatigued below the average standard (from stress of habit, from overstressed at work, from worry, anxiety, fear, injury, etc.) may become the location of the crisis of systemic latent tissue acidosis. The symptoms are presented differently depending upon which organ is being affected. Which is what makes it appear as if every symptom complex is a separate and distinct disease. You need to begin thinking inside the box and make your box bigger.
I give thanks to this new light and knowledge shed upon nomen culture naming disease by the philosophy of The New Biology(R), every symptom complex goes back to the one and only cause of all so-called cancers, namely systemic latent tissue acidosis. To find the cause of all symptomologies – lung cancer, breast cancer, brain cancer, bowel cancer, pancreatic cancer, thyroid cancer, and prostate cancer – you start with colds and catarrh, and watch the pathology as is it travels from irritation to catarrh to inflammation to induration to ulceration and finally to degeneration or cancer – Nothing more than rotting degenerating tissues, organs or glands. And what is causing this transformation or the degeneration of the cell(s), including the gene transmutation? It is simply the spoiling of the cell(s) due to the build-up of dietary, respiratory, environmental and/or metabolic acids, which have not been properly eliminated through urination, defecation, respiration or perspiration!
Have you ever opened a refrigerator and smelt the spoiling of food at the back? What you are smelling is the acidic wastes from spoiling food! It’s not some germ, it’s not some virus, it’s not some mold that’s breaking the food down, it’s the acidic waste products that are breaking the tissue down and giving rise to the symptomatology. Mold is like a smoking gun, the bullet being the acid. And yet it’s not the bullet or the acid that kills, and surely not the smoke or some gene mutation, or some bacteria or virus, but it is the person himself or herself that is pulling the acidic lifestyle and dietary trigger which then releases the acids that then tenderizes or spoils or rots the cells that make up your tissues, organs and glands. And, a cancerous condition always expresses itself first in the weakest parts of the body.
Nature’s order is interfered with by innovating acidic lifestyle and dietary habits until acidosis is established.
A vaccination as evidenced by the Spanish flu epidemic or an infection, in truth is literally an out-fection from the same source causing the most vulnerable organ, specifically the bowels, to take on organic or anatomical changes. The organ however has nothing to do with the cause, and directing treatment to the organ is actually compounding the problem. You cannot treat disease when in reality disease is the body in preservation mode trying to re-establish alkaline homeostasis when in a state of systemic acidosis that is affecting the weakest parts of the body, first!
When you realize that breast cancer is the second leading cause of death in women and these fatty tissues (breast areas) are being used by the body to bind or collect acidic waste products in order to protect the organs that sustain life. And, by the way, when one does a mammogram and sees these micro-calcification in the breast tissue, this is an indication of a state of tissue acidosis – the body’s defensive mechanism to relieve or remove or neutralize and solidify acidity that has not been properly eliminated though urination, defecation, respiration or perspiration.
If you are dealing with a cancerous prostate, you are dealing with localized acidity. If you are dealing with lung cancer, you are dealing with localized acidity that has been caused by external or internal forces even though a cancerous condition begins from within. As you take in tobacco smoke, there are acids or toxins or poisons – one being sugar which breaks down to acetaldehyde, which tenderizes and rots the lung tissues. Tobacco smoking is not an addiction of nicotine alone. It is an addiction of sugar, which causes excess acidity in the lung causing lung cancer. The cause is always constant, ever-present, always the same, only the effects change. To illustrate, a catarrh of the stomach presents first irritation, then inflammation, then ulceration, induration and finally degeneration or a cancerous stomach. Cancer is not at the first, it’s the culmination of deteriorating or broken tissue spoiled by an over-acidic stomach from an over-acidic lifestyle and diet.
Most people in the world are challenged with the symptomatology of indigestion, which can include acid reflux, bloating, heartburn, burping, diarrhea, or even constipation. The proper way to study a disease is to study health in every aspect. Disease is perverted health. Cancer is perverted health – any influence that lowers energy becomes disease-producing.
There’s an important question now to answer. Why do I crave sugar? It’s interesting when doing an MRI or a CAT scan. What is used but radioactive sugar that is taken up by the acidic cancerous cells – not cancer cells because we don’t have cancer cells, we have acidic cells or cancerous cells – cells that have been spoiled by the environment in which they live. So sugar cravings are the body’s need for sustainable energy. And energy can only be transported through a matrix of salt. Therefore sugar cravings are the body’s needs for salt, not sugar. I would suggest that sugar is an acid of cellular transformation – a waste product – not a product of energy, but a by-product of what the body truly uses which is electrical potential in the form of electrons.
The body doesn’t use carbohydrates, the body uses electrons to run. The body is electrical. And sugar is nothing more than an acidic waste product of cellular breakdown and transformation. Isn’t that what happens to the banana? As the banana moves from irritation to inflammation to induration and then to cancer, going from green to yellow to brown, getting its “liver spots” the same way you get liver spots, through excess fermentation and rotting. You do not say the banana has cancer, you say the banana is spoiling. In the same way you shouldn’t say that the lung has cancer but rather that the lung is spoiling – it is cancerous. Cancer is not a noun but an adjective expressing the process of cellular transformation. Again, sugar is the waste product. In fact, that’s why a banana gets sweeter and sweeter as it ferments. Consistently in my cancer research I see that we have a release of sugar from the breakdown of tissues, organs or glands. And to overcome sugar cravings you don’t have to eat sugar, you need to eat more salt. The secondary metabolites of this primary acid or sugar are acetaldehyde and ethanol alcohol. So sugar cravings are the body’s signal that the body needs more sustainable energy. You need energy to remove the acids of diet and metabolism – the body utilizing electrons for energy purposes. Food, water, sun, minerals, vitamins, drugs… are common choices made by us to achieve sustainable energy, but yet what you are looking for are the electrons from these sources. And your choices will determine whether or not your cravings will lead to true sustainable energy which maintains the alkaline integrity of the fluids of body and therefore the integrity of the tissues, organs and glands, or gives you false energy which creates this over-acidic state that leads to latent tissue acidosis which begins the process of spoiling of the tissues, organs and glands and finally a degenerative or cancerous condition.
Sugar stimulates and gives the body a deceptive quick-fix – it’s illusionary – whereas salt provides the matrix of life and gives your body the rise in sustainable energy, over a longer period of time, without the high and extreme lows that come from eating an acid – whether it be sugar or any other acidic foods or drinks.
It is the skin that suffers most, because if the body can’t eliminate the acids that are created through energy use, it throws the acidic wastes out into the connective and fatty tissues and into the lymphatic system. This is why the lymphatic system is so critical in the prevention of cancer and in the treatment of cancer, because it is the lymphatic system that is the vacuum cleaner of the acids that are in the interstitial fluids of the body, pulling these poisonous acids out in order to maintain the integrity of the tissue through diaphramic breathing and perspiration (that is if you are perspiring, which is one of the most important things you need to do on a daily basis to remove cancer causing acids). If you cannot eliminate your acidic wastes completely through urination, respiration or defecation then your body urinates through the skin – which is why there is over a million cases of skin cancer a year in the United States alone. It’s not talked about. Why? Because the etiology of skin cancer is not understood. It is unknown. Scientists don’t know what causes basal cell carcinoma, melanoma, they do not understand it because they don’t understand latent tissue acidosis and the importance of the lymphatic system as the vacuum cleaner to remove poisonous acidic wastes out via the kidneys and through perspiration. But people are not exercising, and this is why obesity and a lack of exercise have been associated with cancer. Yet when you are moving your body you are moving the acidic wastes out of the connective and fatty tissues, organs and glands. The lymphatic system, unlike the circulatory system, does not have a pump (the heart), it actually flows through movement. It is the diaphragm muscle that acts as a pump for the lymphatic system that moves acidic wastes through the system – out through perspiration or back into general circulation to be eliminated through urination.
And if you have a cancerous condition you have to pee your way to health. Because cancer is not a cell, but a poisonous acidic liquid. A cancer cell is a cell that has been spoiled or poisoned by the metabolic, respiratory, environmental and/or gastrointestinal acids that are produced internally, or may be taken in via the lungs or skin. That’s when the body will go into the preservation mode by forming fibrous materials, which cross-link to encapsulate the spoiled cancerous cells and thus forming the protective tumor. Hence, the tumor is the body’s protective mechanism to encapsulate spoiled or poisoned acidic cells from excess acidic wastes which have not been properly eliminated through urination, defecation, respiration and/or perspiration. The tumor is the body’s solution to protect healthy cells that make up tissues, organs and glands of the body. So, the tumor is not the problem. Let the tumor go. Let it do its job. The focus must be placed not on the tumor but on the internal environment around the tumor, which is full of acidic cells. One of the common acids which is in higher concentration around all tumors is lactic acid. Lactic acid is a by-product of metabolism when you are in a state of oxygen deprivation. Think of any cancerous condition as a systemic acidic condition that affects first the weakest parts of the body, not a local problem that metastasizes. You see metastasis is localized acids that spoil other cells much like a rotten apple placed in the center of a bushel of healthy apples will spoil the whole bushel. I call this the ‘domino effect’ where one acidic cell spoils another healthy cell causing a chain reaction. The body stops the ‘domino effect’ by forming the tumor around the cancerous or acidic body cells.
Therefore, there is no such thing as a cancer cell. A cancer cell in reality is a cancerous cell. Cancer is an adjective expressing the spoiling body cells that are rotting in an over-acidic environment. A cancerous cell was once a healthy cell that has been spoiled from an over-acidic lifestyle and diet and the body’s inability to remove these acids through the proper channels of elimination.
The only solution to the acidic toxic liquids that poison our body cells causing the effect that medical doctors call cancer, is to change the environment. It has to be a contextual approach. You must restore and maintain the alkaline design of the human body if you want to prevent or reverse a cancerous condition. This has been my great discovery of the 21st century – that the human organism is alkaline by design and acidic by function. Every part of the body that makes up every anatomical element, that makes up your genetic material, that makes up your body cells, every single part has to be bathed in an alkaline fluid which needs to be purified every 24 hours to remain healthy.
Early in the 19th century, beginning on January 17, 1912, a famous French physiologist of the Rockefeller Institute and Nobel Prize winner, Dr. Alexis Carrel, removed a very small piece of heart muscle from an un-hatched chicken embryo—still warm and living—and placed it in fresh nutrient solution in a glass flask of his own design. He transferred the tissue every forty-eight hours, during which time it doubled in size and had to be trimmed before being moved to its new flask. Every time he moved the heart he would put it into an alkaline saline solution with the appropriate alkalizing minerals. Twenty years later the heart tissue was still growing. Keep in mind that the average chicken lives for 5 – 7 years. So, after getting bored of singing “Happy Birthday” to the chicken heart for over twenty years he decided to pull the plug and not change the fluids every 48 hours and the heart finally died.
This is a very important discovery, which very few people know about. Why? Because it answers the question about why cells live and why cells die. You see, the life expectancy of the human cell is infinite. The body cells become compromised by their environment. Once you understand that matter cannot be created nor can it be destroyed it can only change its form or function, then you will realize that the environment is everything, the terrain is everything, and the cell is subservient to that.
The secret to Dr. Carrel’s chicken heart surviving for twenty years lies in this knowledge, this New Biology, this new way of living and thinking as we expand the box rather than thinking outside the box, that the cell is only as healthy as the alkaline fluids it is bathed in. The heart is only as healthy as the cells and the fluids they are bathed in. If you have any cancerous condition, this cancerous condition is the expression of your internal environment. The human cell will only breakdown in an acidic environment and become cancerous.
Carrel’s experiment brought me to the modern New Biology, the new understanding, the new expansion, the new medicine and the new definition of cancer – that the composition of our body fluids that bath the outside of our cells must be controlled very carefully from moment to moment and day-to-day with no single important constituent varying more than a one percent. This condition of health can be controlled and you can do it yourself!
In 1932 Otto Warburg received his Nobel Prize in medicine for discovering the cause of cancer. He described it as a cell changing its mode of respiration, its mode of metabolism – from respiration to fermentation. He suggested that cancer was the result of acidic environment, a state of oxygen deprivation. Warburg also wrote a paper entitled, “The Prime Cause and Prevention of Cancer.” He states: “There is no disease whose prime cause is better known – over acidity.”
When you understand this you realize that all conditions of cancer potentially can be reversed if the treatments are focused on the fluids and not the cells of the body. Therefore it doesn’t matter what the cancerous condition is, because cancer is not the cause but the effect of an over-acidic lifestyle and diet which is the cause of cancer. It’s you pulling the acidic lifestyle and dietary trigger that causes cancer. You do NOT get CANCER – You DO CANCER with your daily lifestyle and dietary choices!
After 30 years of doing blood research, after looking at thousands and thousands of cancerous patients, I’ve never seen healthy blood or an alkaline internal environment – whether testing the pH of the saliva, or the urine, or the blood, or the sweat, or the tears – they are all acidic in an over-acidic internal environment. I have come to understand that the human organism is alkaline by design and acidic by function, and if you maintain this alkaline design of your body through an alkaline lifestyle and diet you WiLL prevent all cancerous conditions. For the cure of cancer is not found in its treatment, because a cancerous condition is the body in preservation mode trying to restore its alkalinity. The cure for a cancerous condition will not be found in its treatment of the tissues but in maintaining the alkaline design of the body fluids.
As Thomas Edison said: “The doctor of the future will give no medicine, but will involve the patient in the proper use of food, fresh air and exercise.
The future is here and NOW and is found in the following chapters of pH Miracle for Cancer.
My hope is The pH Miracle for Cancer will expand your box of truth and knowledge to protect you from the acidic condition medical science calls Cancer.
To pre-order The pH Miracle for Cancer go to: http://www.phoreveryoung.com
The digital version of The pH Miracle for Cancer is NOW Available just order on line at: http://www.phoreveryoung.com
1. Hanna G, Fontanella A, Palmer G, Shan S, Radiloff DR, Zhao Y, Irwin D, Hamilton K, Boico A, Piantadosi CA, Blueschke G, Dewhirst M, McMahon T, Schroeder T. Automated measurement of blood flow velocity and direction and hemoglobin oxygen saturation in the rat lung using intravital microscopy. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2013;304(2):L86–L91.[PubMed]
2. Yang, K.R., Mooney, S., Zarif, J.C., Coffey, D.S., Taichman, R.S. & Pienta, K.J. (2014). Niche inheritance: a cooperative pathway to enhance cancer cell fitness through ecosystem engineering. Journal of Cellular Biochemistry. [PMC free article] [PubMed]
3. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nature reviews. Cancer. 2004;4(11):891–899. [PubMed]
4. Lee WY, Huang SC, Hsu KF, Tzeng CC, Shen WL. Roles for hypoxia-regulated genes during cervical carcinogenesis: somatic evolution during the hypoxia-glycolysis-acidosis sequence. Gynecologic Oncology. 2008;108(2):377–384. [PubMed]
5. Ibrahim-Hashim A, Cornnell HH, Abrahams D, Lloyd M, Bui M, Gillies RJ, Gatenby RA. Systemic buffers inhibit carcinogenesis in TRAMP mice. The Journal of Urology. 2012;188(2):624–631.[PMC free article] [PubMed]
6. Estrella V, Chen T, Lloyd M, Wojtkowiak J, Cornnell HH, Ibrahim-Hashim A, Bailey K, Balagurunathan Y, Rothberg JM, Sloane BF, Johnson J, Gatenby RA, Gillies RJ. Acidity generated by the tumor microenvironment drives local invasion. Cancer Research. 2013;73(5):1524–1535.[PMC free article] [PubMed]
7. Robey IF, Baggett BK, Kirkpatrick ND, Roe DJ, Dosescu J, Sloane BF, Hashim AI, Morse DL, Raghunand N, Gatenby RA, Gillies RJ. Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer Research. 2009;69(6):2260–2268. [PMC free article] [PubMed]
8. Warburg O. On the origin of cancer cells. Science (New York, N.Y.) 1956;123(3191):309–314.[PubMed]
9. Zu XL, Guppy M. Cancer metabolism: facts, fantasy, and fiction. Biochemical and Biophysical Research Communications. 2004;313(3):459–465. [PubMed]
10. Kroemer G. Mitochondria in cancer. Oncogene. 2006;25(34):4630–4632. [PubMed]
11. Hume DA, Weidemann MJ. Role and regulation of glucose metabolism in proliferating cells. Journal of the National Cancer Institute. 1979;62(1):3–8. [PubMed]
12. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science (New York, N.Y.) 2009;324(5930):1029–1033.[PMC free article] [PubMed]
13. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(49):19345–19350. [PMC free article] [PubMed]
14. Lemons JM, Feng XJ, Bennett BD, Legesse-Miller A, Johnson EL, Raitman I, Pollina EA, Rabitz HA, Rabinowitz JD, Coller HA. Quiescent fibroblasts exhibit high metabolic activity. PLoS Biology. 2010;8(10):e1000514. [PMC free article] [PubMed]
15. Gillies RJ, Robey I, Gatenby RA. Causes and consequences of increased glucose metabolism of cancers. Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine. 2008;49(Suppl 2):24S–42S. [PubMed]
16. Gatenby RA. The potential role of transformation-induced metabolic changes in tumor-host interaction. Cancer Research. 1995;55(18):4151–4156. [PubMed]
17. Gillies RJ, Martinez-Zaguilan R, Martinez GM, Serrano R, Perona R. Tumorigenic 3T3 cells maintain an alkaline intracellular pH under physiological conditions. Proceedings of the National Academy of Sciences of the United States of America. 1990;87(19):7414–74
18. [PMC free article] [PubMed]18. Gatenby RA, Gillies RJ. A microenvironmental model of carcinogenesis. Nature Reviews. Cancer. 2008;8(1):56–61. [PubMed]
19. Garcia SB, Novelli M, Wright NA. The clonal origin and clonal evolution of epithelial tumours. International Journal of Experimental Pathology. 2000;81(2):89–116. [PMC free article] [PubMed]
20. Nowell PC. The clonal evolution of tumor cell populations. Science (New York, N.Y.) 1976;194(4260):23–28. [PubMed]
21. Ilyas M, Straub J, Tomlinson IP, Bodmer WF. Genetic pathways in colorectal and other cancers. European Journal of Cancer (Oxford, England: 1990) 1999;35(3):335–351. [PubMed]
22. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–767.[PubMed]
23. Silva AS, Gatenby RA, Gillies RJ, Yunes JA. A quantitative theoretical model for the development of malignancy in ductal carcinoma in situ. Journal of Theoretical Biology. 2010;262(4):601–613. [PubMed]
24. Gatenby RA, Smallbone K, Maini PK, Rose F, Averill J, Nagle RB, Worrall L, Gillies RJ. Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer. British Journal of Cancer. 2007;97(5):646–653. [PMC free article] [PubMed]
25. Smallbone K, Gatenby RA, Gillies RJ, Maini PK, Gavaghan DJ. Metabolic changes during carcinogenesis: potential impact on invasiveness. Journal of Theoretical Biology. 2007;244(4):703–713.[PubMed]
26. Wykoff CC, Beasley N, Watson PH, Campo L, Chia SK, English R, Pastorek J, Sly WS, Ratcliffe P, Harris AL. Expression of the hypoxia-inducible and tumor-associated carbonic anhydrases in ductal carcinoma in situ of the breast. The American Journal of Pathology. 2001;158(3):1011–1019.[PMC free article] [PubMed]
27. Huber V, De Milito A, Harguindey S, Reshkin SJ, Wahl ML, Rauch C, Chiesi A, Pouyssegur J, Gatenby RA, Rivoltini L, Fais S. Proton dynamics in cancer. Journal of Translational Medicine. 2010;8:57.[PMC free article] [PubMed]
28. Webb BA, Chimenti M, Jacobson MP, Barber DL. Dysregulated pH: a perfect storm for cancer progression. Nature Reviews. Cancer. 2011;11(9):671–677. [PubMed]
29. Rich IN, Worthington-White D, Garden OA, Musk P. Apoptosis of leukemic cells accompanies reduction in intracellular pH after targeted inhibition of the Na(+)/H(+) exchanger. Blood. 2000;95(4):1427–1434. [PubMed]
30. Che XF, Zheng CL, Akiyama S, Tomoda A. 2-Aminophenoxazine-3-one and 2-amino-4,4alpha-dihydro-4alpha,7-dimethyl-3H-phenoxazine-3-one cause cellular apoptosis by reducing higher intracellular pH in cancer cells. Proceedings of the Japan Academy. Series B, Physical and Biological Sciences. 2011;87(4):199–213. [PMC free article] [PubMed]
31. Nagata H, Che XF, Miyazawa K, Tomoda A, Konishi M, Ubukata H, Tabuchi T. Rapid decrease of intracellular pH associated with inhibition of Na+/H+ exchanger precedes apoptotic events in the MNK45 and MNK74 gastric cancer cell lines treated with 2-aminophenoxazine-3-one. Oncology Reports. 2011;25(2):341–346. [PubMed]
32. Di Sario A, Bendia E, Omenetti A, De Minicis S, Marzioni M, Kleemann HW, Candelaresi C, Saccomanno S, Alpini G, Benedetti A. Selective inhibition of ion transport mechanisms regulating intracellular pH reduces proliferation and induces apoptosis in cholangiocarcinoma cells. Digestive and Liver Disease: Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2007;39(1):60–69. [PubMed]
33. Roepe PD. Analysis of the steady-state and initial rate of doxorubicin efflux from a series of multidrug-resistant cells expressing different levels of P-glycoprotein. Biochemistry. 1992;31(50):12555–12564. [PubMed]
34. Murakami T, Shibuya I, Ise T, Chen ZS, Akiyama S, Nakagawa M, Izumi H, Nakamura T, Matsuo K, Yamada Y, Kohno K. Elevated expression of vacuolar proton pump genes and cellular PH in cisplatin resistance. International Journal of Cancer. Journal International Du Cancer. 2001;93(6):869–874.[PubMed]
35. Martinez-Zaguilan R, Raghunand N, Lynch RM, Bellamy W, Martinez GM, Rojas B, Smith D, Dalton WS, Gillies RJ. pH and drug resistance. I. Functional expression of plasmalemmal V-type H+-ATPase in drug-resistant human breast carcinoma cell lines. Biochemical Pharmacology. 1999;57(9):1037–1046.[PubMed]
36. Keizer HG, Joenje H. Increased cytosolic pH in multidrug-resistant human lung tumor cells: effect of verapamil. Journal of the National Cancer Institute. 1989;81(9):706–709. [PubMed]
37. Altan N, Chen Y, Schindler M, Simon SM. Defective acidification in human breast tumor cells and implications for chemotherapy. The Journal of Experimental Medicine. 1998;187(10):1583–1598.[PMC free article] [PubMed]
38. Belhoussine R, Morjani H, Sharonov S, Ploton D, Manfait M. Characterization of intracellular pH gradients in human multidrug-resistant tumor cells by means of scanning microspectrofluorometry and dual-emission-ratio probes. International Journal of Cancer. Journal International Du Cancer. 1999;81(1):81–89. [PubMed]
39. Becelli R, Renzi G, Morello R, Altieri F. Intracellular and extracellular tumor pH measurement in a series of patients with oral cancer. The Journal of Craniofacial Surgery. 2007;18(5):1051–1054. [PubMed]
40. Raghunand N, Mahoney B, van Sluis R, Baggett B, Gillies RJ. Acute metabolic alkalosis enhances response of C3H mouse mammary tumors to the weak base mitoxantrone. Neoplasia (New York, N.Y.) 2001;3(3):227–235. [PMC free article] [PubMed]
41. Simon S, Roy D, Schindler M. Intracellular pH and the control of multidrug resistance. Proceedings of the National Academy of Sciences of the United States of America. 1994;91(3):1128–1132.[PMC free article] [PubMed]
42. Ouar Z, Bens M, Vignes C, Paulais M, Pringel C, Fleury J, Cluzeaud F, Lacave R, Vandewalle A. Inhibitors of vacuolar H+-ATPase impair the preferential accumulation of daunomycin in lysosomes and reverse the resistance to anthracyclines in drug-resistant renal epithelial cells. The Biochemical Journal. 2003;370(Pt 1):185–193. [PMC free article] [PubMed]
43. Federici C, Petrucci F, Caimi S, Cesolini A, Logozzi M, Borghi M, D’Ilio S, Lugini L, Violante N, Azzarito T, Majorani C, Brambilla D, Fais S. Exosome release and low pH belong to a framework of resistance of human melanoma cells to cisplatin. PloS One. 2014;9(2):e88193. [PMC free article][PubMed]
44. Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A, Coscia C, Iessi E, Logozzi M, Molinari A, Colone M, Tatti M, Sargiacomo M, Fais S. Microenvironmental pH is a key factor for exosome traffic in tumor cells. The Journal of Biological Chemistry. 2009;284(49):34211–34222.[PMC free article] [PubMed]
45. Fais S. Proton pump inhibitor-induced tumour cell death by inhibition of a detoxification mechanism. Journal of Internal Medicine. 2010;267(5):515–525. [PubMed]
46. Nishi T, Forgac M. The vacuolar (H+)-ATPases—nature’s most versatile proton pumps. Nature Reviews. Molecular Cell Biology. 2002;3(2):94–103. [PubMed]
47. Sennoune SR, Martinez-Zaguilan R. Plasmalemmal vacuolar H+-ATPases in angiogenesis, diabetes and cancer. Journal of Bioenergetics and Biomembranes. 2007;39(5–6):427–433. [PubMed]
48. Chung C, Mader CC, Schmitz JC, Atladottir J, Fitchev P, Cornwell ML, Koleske AJ, Crawford SE, Gorelick F. The vacuolar-ATPase modulates matrix metalloproteinase isoforms in human pancreatic cancer. Laboratory Investigation; A Journal of technical Methods and Pathology. 2011;91(5):732–743.[PMC free article] [PubMed]
49. Sennoune SR, Bakunts K, Martinez GM, Chua-Tuan JL, Kebir Y, Attaya MN, Martinez-Zaguilan R. Vacuolar H+-ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity. American Journal of Physiology. Cell Physiology. 2004;286(6):C1443–C1452.[PubMed]
50. Martinez-Zaguilan R, Lynch RM, Martinez GM, Gillies RJ. Vacuolar-type H(+)-ATPases are functionally expressed in plasma membranes of human tumor cells. The American Journal of Physiology. 1993;265(4 Pt 1):C1015–C1029. [PubMed]
51. Xu J, Xie R, Liu X, Wen G, Jin H, Yu Z, Jiang Y, Zhao Z, Yang Y, Ji B, Dong H, Tuo B. Expression and functional role of vacuolar H(+)-ATPase in human hepatocellular carcinoma. Carcinogenesis. 2012;33(12):2432–2440. [PubMed]
52. Avnet S, Di Pompo G, Lemma S, Salerno M, Perut F, Bonuccelli G, Granchi D, Zini N, Baldini N. V-ATPase is a candidate therapeutic target for Ewing sarcoma. Biochimica et Biophysica Acta. 2013;1832(8):1105–1116. [PubMed]
53. Philippe JM, Dubois JM, Rouzaire-Dubois B, Cartron PF, Vallette F, Morel N. Functional expression of V-ATPases in the plasma membrane of glial cells. Glia. 2002;37(4):365–373. [PubMed]
54. Hinton A, Sennoune SR, Bond S, Fang M, Reuveni M, Sahagian GG, Jay D, Martinez-Zaguilan R, Forgac M. Function of a subunit isoforms of the V-ATPase in pH homeostasis and in vitro invasion of MDA-MB231 human breast cancer cells. The Journal of Biological Chemistry. 2009;284(24):16400–16408. [PMC free article] [PubMed]
55. Lu Q, Lu S, Huang L, Wang T, Wan Y, Zhou CX, Zhang C, Zhang Z, Li X. The expression of V-ATPase is associated with drug resistance and pathology of non-small cell lung cancer. Diagnostic Pathology. 2013;8:145. [PMC free article] [PubMed]
56. Michel V, Licon-Munoz Y, Trujillo K, Bisoffi M, Parra KJ. Inhibitors of vacuolar ATPase proton pumps inhibit human prostate cancer cell invasion and prostate-specific antigen expression and secretion. International Journal of Cancer. Journal International Du Cancer. 2013;132(2):E1–E10. [PMC free article][PubMed]
57. Nishisho T, Hata K, Nakanishi M, Morita Y, Sun-Wada GH, Wada Y, Yasui N, Yoneda T. The a3 isoform vacuolar type H(+)-ATPase promotes distant metastasis in the mouse B16 melanoma cells. Molecular Cancer Research: MCR. 2011;9(7):845–855. [PubMed]
58. Luciani F, Spada M, De Milito A, Molinari A, Rivoltini L, Montinaro A, Marra M, Lugini L, Logozzi M, Lozupone F, Federici C, Iessi E, Parmiani G, Arancia G, Belardelli F, Fais S. Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs. Journal of the National Cancer Institute. 2004;96(22):1702–1713. [PubMed]
59. De Milito A, Marino ML, Fais S. A rationale for the use of proton pump inhibitors as antineoplastic agents. Current Pharmaceutical Design. 2012;18(10):1395–1406. [PubMed]
60. Xu K, Mao X, Mehta M, Cui J, Zhang C, Mao F, Xu Y. Elucidation of how cancer cells avoid acidosis through comparative transcriptomic data analysis. PloS One. 2013;8(8):e71177. [PMC free article][PubMed]
61. Katara, G.K., Jaiswal, M.K., Kulshrestha, A., Kolli, B., Gilman-Sachs, A. & Beaman, K.D. (2013). Tumor-associated vacuolar ATPase subunit promotes tumorigenic characteristics in macrophages. Oncogene. [PubMed]
62. Huang L, Lu Q, Han Y, Li Z, Zhang Z, Li X. ABCG2/V-ATPase was associated with the drug resistance and tumor metastasis of esophageal squamous cancer cells. Diagnostic Pathology. 2012;7:180.[PMC free article] [PubMed]
63. Garcia-Garcia A, Perez-Sayans Garcia M, Rodriguez MJ, Antunez-Lopez J, Barros-Angueira F, Somoza-Martin M, Gandara-Rey JM, Aguirre-Urizar JM. Immunohistochemical localization of C1 subunit of V-ATPase (ATPase C1) in oral squamous cell cancer and normal oral mucosa. Biotechnic & Histochemistry: Official Publication of the Biological Stain Commission. 2012;87(2):133–139. [PubMed]
64. Ohta T, Numata M, Yagishita H, Futagami F, Tsukioka Y, Kitagawa H, Kayahara M, Nagakawa T, Miyazaki I, Yamamoto M, Iseki S, Ohkuma S. Expression of 16 kDa proteolipid of vacuolar-type H(+)-ATPase in human pancreatic cancer. British Journal of Cancer. 1996;73(12):1511–1517. [PMC free article][PubMed]
65. De Milito A, Canese R, Marino ML, Borghi M, Iero M, Villa A, Venturi G, Lozupone F, Iessi E, Logozzi M, Della Mina P, Santinami M, Rodolfo M, Podo F, Rivoltini L, Fais S. pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. International Journal of Cancer. Journal International Du Cancer. 2010;127(1):207–219. [PubMed]
66. Malo ME, Fliegel L. Physiological role and regulation of the Na+/H+ exchanger. Canadian Journal of Physiology and Pharmacology. 2006;84(11):1081–1095. [PubMed]
67. Daniel C, Bell C, Burton C, Harguindey S, Reshkin SJ, Rauch C. The role of proton dynamics in the development and maintenance of multidrug resistance in cancer. Biochimica et Biophysica Acta. 2013;1832(5):606–617. [PubMed]
68. Harguindey S, Arranz JL, Polo Orozco JD, Rauch C, Fais S, Cardone RA, Reshkin SJ. Cariporide and other new and powerful NHE1 inhibitors as potentially selective anticancer drugs–an integral molecular/biochemical/metabolic/clinical approach after one hundred years of cancer research. Journal of Translational Medicine. 2013;11:282. [PMC free article] [PubMed]
69. Amith SR, Fliegel L. Regulation of the Na+/H+ exchanger (NHE1) in breast cancer metastasis. Cancer Research. 2013;73(4):1259–1264. [PubMed]
70. Magalhaes MA, Larson DR, Mader CC, Bravo-Cordero JJ, Gil-Henn H, Oser M, Chen X, Koleske AJ, Condeelis J. Cortactin phosphorylation regulates cell invasion through a pH-dependent pathway. The Journal of Cell Biology. 2011;195(5):903–920. [PMC free article] [PubMed]
71. Bourguignon LY, Singleton PA, Diedrich F, Stern R, Gilad E. CD44 interaction with Na+-H+ exchanger (NHE1) creates acidic microenvironments leading to hyaluronidase-2 and cathepsin B activation and breast tumor cell invasion. The Journal of Biological Chemistry. 2004;279(26):26991–27007. [PubMed]
72. Halestrap AP. The monocarboxylate transporter family—structure and functional characterization. IUBMB Life. 2012;64(1):1–9. [PubMed]
73. Ganapathy V, Thangaraju M, Prasad PD. Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond. Pharmacology & Therapeutics. 2009;121(1):29–40. [PubMed]
74. Pinheiro C, Reis RM, Ricardo S, Longatto-Filho A, Schmitt F, Baltazar F. Expression of monocarboxylate transporters 1, 2, and 4 in human tumours and their association with CD147 and CD44. Journal of Biomedicine & Biotechnology. 2010;2010:427694. [PMC free article] [PubMed]
75. Miranda-Goncalves V, Honavar M, Pinheiro C, Martinho O, Pires MM, Pinheiro C, Cordeiro M, Bebiano G, Costa P, Palmeirim I, Reis RM, Baltazar F. Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets. Neuro-Oncology. 2013;15(2):172–188.[PMC free article] [PubMed]
76. Wahl ML, Owen JA, Burd R, Herlands RA, Nogami SS, Rodeck U, Berd D, Leeper DB, Owen CS. Regulation of intracellular pH in human melanoma: potential therapeutic implications. Molecular Cancer Therapeutics. 2002;1(8):617–628. [PubMed]
77. Fang J, Quinones QJ, Holman TL, Morowitz MJ, Wang Q, Zhao H, Sivo F, Maris JM, Wahl ML. The H+-linked monocarboxylate transporter (MCT1/SLC16A1): a potential therapeutic target for high-risk neuroblastoma. Molecular Pharmacology. 2006;70(6):2108–2115. [PubMed]
78. Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, Feron O, Dewhirst MW. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. The Journal of Clinical Investigation. 2008;118(12):3930–3942. [PMC free article] [PubMed]
79. Swietach P, Hulikova A, Vaughan-Jones RD, Harris AL. New insights into the physiological role of carbonic anhydrase IX in tumour pH regulation. Oncogene. 2010;29(50):6509–6521. [PubMed]
80. Swietach P, Vaughan-Jones RD, Harris AL. Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metastasis Reviews. 2007;26(2):299–310. [PubMed]
81. Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, Sibtain A, Wilson GD, Turley H, Talks KL, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL. Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Research. 2000;60(24):7075–7083. [PubMed]
82. Pastorek J, Pastorekova S, Callebaut I, Mornon JP, Zelnik V, Opavsky R, Zat’ovicova M, Liao S, Portetelle D, Stanbridge EJ. Cloning and characterization of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and a putative helix-loop-helix DNA binding segment. Oncogene. 1994;9(10):2877–2888. [PubMed]
83. De Simone G, Supuran CT. Carbonic anhydrase IX: biochemical and crystallographic characterization of a novel antitumor target. Biochimica et Biophysica Acta. 2010;1804(2):404–409. [PubMed]
84. Pastorekova S, Parkkila S, Parkkila AK, Opavsky R, Zelnik V, Saarnio J, Pastorek J. Carbonic anhydrase IX, MN/CA IX: analysis of stomach complementary DNA sequence and expression in human and rat alimentary tracts. Gastroenterology. 1997;112(2):398–408. [PubMed]
85. Chia SK, Wykoff CC, Watson PH, Han C, Leek RD, Pastorek J, Gatter KC, Ratcliffe P, Harris AL. Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2001;19(16):3660–3668. [PubMed]
86. Giatromanolaki A, Koukourakis MI, Sivridis E, Pastorek J, Wykoff CC, Gatter KC, Harris AL. Expression of hypoxia-inducible carbonic anhydrase-9 relates to angiogenic pathways and independently to poor outcome in non-small cell lung cancer. Cancer Research. 2001;61(21):7992–7998. [PubMed]
87. Generali D, Fox SB, Berruti A, Brizzi MP, Campo L, Bonardi S, Wigfield SM, Bruzzi P, Bersiga A, Allevi G, Milani M, Aguggini S, Dogliotti L, Bottini A, Harris AL. Role of carbonic anhydrase IX expression in prediction of the efficacy and outcome of primary epirubicin/tamoxifen therapy for breast cancer. Endocrine-Related Cancer. 2006;13(3):921–930. [PubMed]
88. Roos A, Boron WF. Intracellular pH. Physiological Reviews. 1981;61(2):296–434. [PubMed]
89. Cardone RA, Casavola V, Reshkin SJ. The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nature Reviews. Cancer. 2005;5(10):786–795. [PubMed]
90. Harguindey S, Orive G, Luis Pedraz J, Paradiso A, Reshkin SJ. The role of pH dynamics and the Na+/H+ antiporter in the etiopathogenesis and treatment of cancer. Two faces of the same coin–one single nature. Biochimica et Biophysica Acta. 2005;1756(1):1–24. [PubMed]
91. Reshkin SJ, Cardone RA, Harguindey S. Na+-H+ exchanger, pH regulation and cancer. Recent Patents on Anti-Cancer Drug Discovery. 2013;8(1):85–99. [PubMed]
92. Harguindey S, Arranz JL, Wahl ML, Orive G, Reshkin SJ. Proton transport inhibitors as potentially selective anticancer drugs. Anticancer Research. 2009;29(6):2127–2136. [PubMed]
93. Perez-Sayans M, Somoza-Martin JM, Barros-Angueira F, Rey JM, Garcia-Garcia A. V-ATPase inhibitors and implication in cancer treatment. Cancer Treatment Reviews. 2009;35(8):707–713. [PubMed]
94. Perez-Sayans M, Somoza-Martin JM, Barros-Angueira F, Diz PG, Rey JM, Garcia-Garcia A. Multidrug resistance in oral squamous cell carcinoma: the role of vacuolar ATPases. Cancer Letters. 2010;295(2):135–143. [PubMed]
95. Bowman EJ, Siebers A, Altendorf K. Bafilomycins: a class of inhibitors of membrane ATPases from microorganisms, animal cells, and plant cells. Proceedings of the National Academy of Sciences of the United States of America. 1988;85(21):7972–7976. [PMC free article] [PubMed]
96. Boyd MR, Farina C, Belfiore P, Gagliardi S, Kim JW, Hayakawa Y, Beutler JA, McKee TC, Bowman BJ, Bowman EJ. Discovery of a novel antitumor benzolactone enamide class that selectively inhibits mammalian vacuolar-type (H+)-atpases. The Journal of Pharmacology and Experimental Therapeutics. 2001;297(1):114–120. [PubMed]
97. Beutler JA, McKee TC. Novel marine and microbial natural product inhibitors of vacuolar ATPase. Current Medicinal Chemistry. 2003;10(9):787–796. [PubMed]
98. Lu X, Qin W, Li J, Tan N, Pan D, Zhang H, Xie L, Yao G, Shu H, Yao M, Wan D, Gu J, Yang S. The growth and metastasis of human hepatocellular carcinoma xenografts are inhibited by small interfering RNA targeting to the subunit ATP6L of proton pump. Cancer Research. 2005;65(15):6843–6849. [PubMed]
99. You H, Jin J, Shu H, Yu B, De Milito A, Lozupone F, Deng Y, Tang N, Yao G, Fais S, Gu J, Qin W. Small interfering RNA targeting the subunit ATP6L of proton pump V-ATPase overcomes chemoresistance of breast cancer cells. Cancer Letters. 2009;280(1):110–119. [PubMed]
100. Capecci J, Forgac M. The function of vacuolar ATPase (V-ATPase) a subunit isoforms in invasiveness of MCF10a and MCF10CA1a human breast cancer cells. The Journal of Biological Chemistry. 2013;288(45):32731–32741. [PMC free article] [PubMed]
101. Mullin JM, Gabello M, Murray LJ, Farrell CP, Bellows J, Wolov KR, Kearney KR, Rudolph D, Thornton JJ. Proton pump inhibitors: actions and reactions. Drug Discovery Today. 2009;14(13–14):647–660. [PubMed]
102. Olbe L, Carlsson E, Lindberg P. A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole. Nature Reviews. Drug Discovery. 2003;2(2):132–139. [PubMed]
103. Ferrari S, Perut F, Fagioli F, Brach Del Prever A, Meazza C, Parafioriti A, Picci P, Gambarotti M, Avnet S, Baldini N, Fais S. Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients’ bed. Journal of Translational Medicine. 2013;11:268. [PMC free article] [PubMed]
104. Chen M, Zou X, Luo H, Cao J, Zhang X, Zhang B, Liu W. Effects and mechanisms of proton pump inhibitors as a novel chemosensitizer on human gastric adenocarcinoma (SGC7901) cells. Cell Biology International. 2009;33(9):1008–1019. [PubMed]
105. Chen M, Huang SL, Zhang XQ, Zhang B, Zhu H, Yang VW, Zou XP. Reversal effects of pantoprazole on multidrug resistance in human gastric adenocarcinoma cells by down-regulating the V-ATPases/mTOR/HIF-1alpha/P-gp and MRP1 signaling pathway in vitro and in vivo. Journal of Cellular Biochemistry. 2012;113(7):2474–2487. [PMC free article] [PubMed]
106. Udelnow A, Kreyes A, Ellinger S, Landfester K, Walther P, Klapperstueck T, Wohlrab J, Henne-Bruns D, Knippschild U, Wurl P. Omeprazole inhibits proliferation and modulates autophagy in pancreatic cancer cells. PloS One. 2011;6(5):e20143. [PMC free article] [PubMed]
107. Spugnini EP, Baldi A, Buglioni S, Carocci F, de Bazzichini GM, Betti G, Pantaleo I, Menicagli F, Citro G, Fais S. Lansoprazole as a rescue agent in chemoresistant tumors: a phase I/II study in companion animals with spontaneously occurring tumors. Journal of Translational Medicine. 2011;9:221.[PMC free article] [PubMed]
108. De Milito A, Iessi E, Logozzi M, Lozupone F, Spada M, Marino ML, Federici C, Perdicchio M, Matarrese P, Lugini L, Nilsson A, Fais S. Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species. Cancer Research. 2007;67(11):5408–5417. [PubMed]
109. Marino ML, Fais S, Djavaheri-Mergny M, Villa A, Meschini S, Lozupone F, Venturi G, Della Mina P, Pattingre S, Rivoltini L, Codogno P, De Milito A. Proton pump inhibition induces autophagy as a survival mechanism following oxidative stress in human melanoma cells. Cell Death & Disease. 2010;1:e87.[PMC free article] [PubMed]
110. Yeo M, Kim DK, Kim YB, Oh TY, Lee JE, Cho SW, Kim HC, Hahm KB. Selective induction of apoptosis with proton pump inhibitor in gastric cancer cells. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2004;10(24):8687–8696. [PubMed]
111. Shen W, Zou X, Chen M, Shen Y, Huang S, Guo H, Zhang L, Liu P. Effect of pantoprazole on human gastric adenocarcinoma SGC7901 cells through regulation of phosphoLRP6 expression in Wnt/beta-catenin signaling. Oncology Reports. 2013;30(2):851–855. [PubMed]
112. Perut F, Avnet S, Fotia C, Baglio SR, Salerno M, Hosogi S, Kusuzaki K, Baldini N. V-ATPase as an effective therapeutic target for sarcomas. Experimental Cell Research. 2014;320(1):21–32. [PubMed]
113. Bellone M, Calcinotto A, Filipazzi P, De Milito A, Fais S, Rivoltini L. The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors. Oncoimmunology. 2013;2(1):e22058. [PMC free article] [PubMed]
114. Calcinotto A, Filipazzi P, Grioni M, Iero M, De Milito A, Ricupito A, Cova A, Canese R, Jachetti E, Rossetti M, Huber V, Parmiani G, Generoso L, Santinami M, Borghi M, Fais S, Bellone M, Rivoltini L. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Research. 2012;72(11):2746–2756. [PubMed]
115. Vishvakarma NK, Singh SM. Immunopotentiating effect of proton pump inhibitor pantoprazole in a lymphoma-bearing murine host: Implication in antitumor activation of tumor-associated macrophages. Immunology Letters. 2010;134(1):83–92. [PubMed]
116. Singh, S., Garg, S.K., Singh, P.P., Iyer, P.G. & El-Serag, H.B. (2013). Acid-suppressive medications and risk of oesophageal adenocarcinoma in patients with Barrett’s oesophagus: a systematic review and meta-analysis. Gut. [PMC free article] [PubMed]
117. Kastelein F, Spaander MC, Steyerberg EW, Biermann K, Valkhoff VE, Kuipers EJ, Bruno MJ, ProBar Study Group Proton pump inhibitors reduce the risk of neoplastic progression in patients with Barrett’s esophagus. Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association. 2013;11(4):382–388. [PubMed]
118. Harley W, Floyd C, Dunn T, Zhang XD, Chen TY, Hegde M, Palandoken H, Nantz MH, Leon L, Carraway KL, 3rd, Lyeth B, Gorin FA. Dual inhibition of sodium-mediated proton and calcium efflux triggers non-apoptotic cell death in malignant gliomas. Brain Research. 2010;1363:159–169.[PMC free article] [PubMed]
119. Yang X, Wang D, Dong W, Song Z, Dou K. Inhibition of Na(+)/H(+) exchanger 1 by 5-(N-ethyl-N-isopropyl) amiloride reduces hypoxia-induced hepatocellular carcinoma invasion and motility. Cancer Letters. 2010;295(2):198–204. [PubMed]
120. Wong P, Kleemann HW, Tannock IF. Cytostatic potential of novel agents that inhibit the regulation of intracellular pH. British Journal of Cancer. 2002;87(2):238–245. [PMC free article] [PubMed]
121. Chang WH, Liu TC, Yang WK, Lee CC, Lin YH, Chen TY, Chang JG. Amiloride modulates alternative splicing in leukemic cells and resensitizes Bcr-AblT315I mutant cells to imatinib. Cancer Research. 2011;71(2):383–392. [PubMed]
122. Miraglia E, Viarisio D, Riganti C, Costamagna C, Ghigo D, Bosia A. Na+/H+ exchanger activity is increased in doxorubicin-resistant human colon cancer cells and its modulation modifies the sensitivity of the cells to doxorubicin. International Journal of Cancer. Journal International Du Cancer. 2005;115(6):924–929. [PubMed]
123. Lauritzen G, Jensen MB, Boedtkjer E, Dybboe R, Aalkjaer C, Nylandsted J, Pedersen SF. NBCn1 and NHE1 expression and activity in DeltaNErbB2 receptor-expressing MCF-7 breast cancer cells: contributions to pHi regulation and chemotherapy resistance. Experimental Cell Research. 2010;316(15):2538–2553. [PubMed]
124. Kellen JA, Mirakian A, Kolin A. Antimetastatic effect of amiloride in an animal tumour model. Anticancer Research. 1988;8(6):1373–1376. [PubMed]
125. Matthews H, Ranson M, Kelso MJ. Anti-tumour/metastasis effects of the potassium-sparing diuretic amiloride: an orally active anti-cancer drug waiting for its call-of-duty? International Journal of Cancer. Journal International Du Cancer. 2011;129(9):2051–2061. [PubMed]
126. Reshkin SJ, Bellizzi A, Cardone RA, Tommasino M, Casavola V, Paradiso A. Paclitaxel induces apoptosis via protein kinase A- and p38 mitogen-activated protein-dependent inhibition of the Na+/H+ exchanger (NHE) NHE isoform 1 in human breast cancer cells. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2003;9(6):2366–2373. [PubMed]
127. Pacchiano F, Carta F, McDonald PC, Lou Y, Vullo D, Scozzafava A, Dedhar S, Supuran CT. Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. Journal of Medicinal Chemistry. 2011;54(6):1896–1902. [PubMed]
128. Touisni N, Maresca A, McDonald PC, Lou Y, Scozzafava A, Dedhar S, Winum JY, Supuran CT. Glycosyl coumarin carbonic anhydrase IX and XII inhibitors strongly attenuate the growth of primary breast tumors. Journal of Medicinal Chemistry. 2011;54(24):8271–8277. [PubMed]
129. Lou Y, McDonald PC, Oloumi A, Chia S, Ostlund C, Ahmadi A, Kyle A, Auf dem Keller U, Leung S, Huntsman D, Clarke B, Sutherland BW, Waterhouse D, Bally M, Roskelley C, Overall CM, Minchinton A, Pacchiano F, Carta F, Scozzafava A, Touisni N, Winum JY, Supuran CT, Dedhar S. Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Research. 2011;71(9):3364–3376. [PubMed]
130. Dubois L, Peeters S, Lieuwes NG, Geusens N, Thiry A, Wigfield S, Carta F, McIntyre A, Scozzafava A, Dogne JM, Supuran CT, Harris AL, Masereel B, Lambin P. Specific inhibition of carbonic anhydrase IX activity enhances the in vivo therapeutic effect of tumor irradiation. Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology. 2011;99(3):424–431. [PubMed]
131. Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. The Biochemical Journal. 1999;343(Pt 2):281–299. [PMC free article] [PubMed]
132. Colen CB, Shen Y, Ghoddoussi F, Yu P, Francis TB, Koch BJ, Monterey MD, Galloway MP, Sloan AE, Mathupala SP. Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study. Neoplasia (New York, N.Y.) 2011;13(7):620–632. [PMC free article][PubMed]
133. Matsubara T, Kusuzaki K, Matsumine A, Shintani K, Satonaka H, Uchida A. Acridine orange used for photodynamic therapy accumulates in malignant musculoskeletal tumors depending on pH gradient. Anticancer Research. 2006;26(1A):187–193. [PubMed]
134. Hashiguchi S, Kusuzaki K, Murata H, Takeshita H, Hashiba M, Nishimura T, Ashihara T, Hirasawa Y. Acridine orange excited by low-dose radiation has a strong cytocidal effect on mouse osteosarcoma. Oncology. 2002;62(1):85–93. [PubMed]
135. Kusuzaki K, Aomori K, Suginoshita T, Minami G, Takeshita H, Murata H, Hashiguchi S, Ashihara T, Hirasawa Y. Total tumor cell elimination with minimum damage to normal tissues in musculoskeletal sarcomas following photodynamic therapy with acridine orange. Oncology. 2000;59(2):174–180.[PubMed]
136. Kusuzaki K, Hosogi S, Ashihara E, Matsubara T, Satonaka H, Nakamura T, Matsumine A, Sudo A, Uchida A, Murata H, Baldini N, Fais S, Marunaka Y. Translational research of photodynamic therapy with acridine orange which targets cancer acidity. Current Pharmaceutical Design. 2012;18(10):1414–1420.[PubMed]
137. Kusuzaki K, Murata H, Matsubara T, Miyazaki S, Shintani K, Seto M, Matsumine A, Hosoi H, Sugimoto T, Uchida A. Clinical outcome of a novel photodynamic therapy technique using acridine orange for synovial sarcomas. Photochemistry and Photobiology. 2005;81(3):705–709. [PubMed]
138. Kusuzaki K, Murata H, Matsubara T, Miyazaki S, Okamura A, Seto M, Matsumine A, Hosoi H, Sugimoto T, Uchida A. Clinical trial of photodynamic therapy using acridine orange with/without low dose radiation as new limb salvage modality in musculoskeletal sarcomas. Anticancer Research. 2005;25(2B):1225–1235. [PubMed]
139. Matsubara T, Kusuzaki K, Matsumine A, Murata H, Nakamura T, Uchida A, Sudo A. Clinical outcomes of minimally invasive surgery using acridine orange for musculoskeletal sarcomas around the forearm, compared with conventional limb salvage surgery after wide resection. Journal of Surgical Oncology. 2010;102(3):271–275. [PubMed]
140. Liu, J., Huang, Y., Kumar, A., Tan, A., Jin, S., Mozhi, A. & Liang, X.J. (2013). pH-Sensitive nano-systems for drug delivery in cancer therapy. Biotechnology Advances. [PubMed]
141. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674.[PubMed]