Misc Inorganic phosphate in the development and treatment of cancer

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Um, don't have cancer but taking a mineral supplement for cancer victims. Percy Weston says that cancer is associated with super phosphate usage.


Inorganic phosphate in the development and treatment of cancer: A Janus Bifrons?
Luigi Sapio and Silvio Naviglio
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Inorganic phosphate (Pi) is an essential nutrient to living organisms. It is required as a component of the energy metabolism, kinase/phosphatase signaling and in the formation and function of lipids, carbohydrates and nucleic acids and, at systemic level, it plays a key role for normal skeletal and dentin mineralization. Pi represents an abundant dietary element and its intestinal absorption is efficient, minimally regulated and typically extends to approximately 70%. Maintenance of proper Pi homeostasis is a critical event and serum Pi level is maintained within a narrow range through an elaborate network of humoral interactions and feedback loops involving intestine, kidney, parathyroid gland and bone, and depends on the activity of a number of hormones, including parathyroid hormone, 1,25-dihydroxy vitamin D, and fibroblast growth factor 23 as major regulators of Pi homeostasis. Notably, Pi intake seemingly continues to increase as a consequence of chronic high-phosphorus (P) diets deriving from the growing consumption of highly processed foods, especially restaurant meals, fast foods, and convenience foods. Several recent reports have generated significant associations between high-P intake or high-serum Pi concentration and morbidity and mortality. Many chronic diseases, including cardiovascular diseases, obesity and even cancer have been proposed to be associated with high-P intakes and high-serum Pi concentrations. On the other hand, there is also evidence that Pi can have antiproliferative effects on some cancer cell types, depending on cell status and genetic background and achieve additive cytotoxic effects when combined with doxorubicin, illustrating its potential for clinical applications and suggesting that up-regulating Pi levels at local sites for brief times, might contribute to the development of novel and cheap modalities for therapeutic intervention in some tumours. Overall, the influence of Pi on cell function and the possible relationship to cancer have to be fully understood and investigated further.
Keywords: Calcium-phosphate nanoparticles, Inorganic phosphate, Cancer, High-phosphorus diets, Phosphorus intake, Doxorubicin, Combination therapy, Naturally occurring molecule, Osteosarcoma
Core tip: Many chronic diseases, including cancer have been proposed to be associated with high-phosphorus intakes and high-serum inorganic phosphate (Pi) concentrations. On the other hand, there is also evidence that Pi can have antiproliferative effects on some cancer cell types, depending on cell status and genetic background and achieve additive cytotoxic effects when combined with doxorubicin, illustrating its potential for clinical applications and suggesting that up-regulating Pi levels at local sites for brief times, might contribute to the development of novel and cheap modalities for therapeutic intervention in some tumors, including triple-negative breast cancer and osteosarcoma.
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One of most important nutrients to living organisms is Inorganic phosphate (Pi). It is required in the ATP formation, kinase/phosphatase signalling and in the synthesis of lipids, carbohydrates and nucleic acids. Furthermore, it plays a key role for normal skeletal and dentin mineralization[1].
Diet represents the main source of Pi intakes, its intestinal absorption is minimally regulated and typically extends to approximately 70%. To maintain Pi levels within a proper range, an elaborate network, including intestine, kidney, parathyroid gland and bone, is involved in a feedback control in which hormones as parathyroid hormone (PTH), 1,25-dihydroxy vitamin D, and fibroblast growth factor 23 (FGF-23) are major regulators of Pi homeostasis[2].
Diets always richer in phosphorus, due to a highly processed food, especially restaurant meals, fast foods, and cheap foods, have increased Pi intake[3,4].
For example, in the United States the consume of phosphorus daily in meals is typically around 1400 mg, as inorganic phosphate (Pi) salts or as a part of organic molecules, that is almost doubled compared to the adult recommended dietary allowance.
The kidney is one of the major regulators of Pi homeostasis and can increase or decrease its capacity to reabsorb Pi; the increased cumulative use of ingredients containing Pi in food processing is now being shown to be potential toxic when it exceeds nutrient needs.
Several recent studies have underlined the relationship between high-Pi intake/high-Pi serum concentration and morbidity and mortality[3,4].
A variety of conditions and diseases, especially cardiovascular diseases, has been spotted in individuals with high-Pi intakes, resulting from chronic high-Pi diets. Other chronic diseases, including type 2 diabetes mellitus, obesity and even cancer have also been proposed to be associated with high-Pi intakes and high-Pi serum concentrations[3-5].
As far as the mechanisms by which high Pi concentrations are linked to tissue damage and/or possibly to influence tumour growth, they are not completely understood and could very likely include a mixture of cell autonomous as well as autocrine, paracrine, and/or endocrine signals.
In particular, although both PTH and FGF-23 are stimulated to decrease the post-meal serum Pi concentration rise, approximately 1 h through the interruption of renal Pi reabsorption, it is hypothesized that if cells are exposed to even a brief high-serum Pi concentration there could be some signal alterations in cell functions leading to negative effects. Moreover, the increase of serum levels of FGF-23 or PTH might be toxic to particular cell types[3,4,6].
Numerous recent studies have reinforced a long-standing hypothesis that there could be a phosphate-sensing mechanism capable of detecting serum and local phosphate variations and of informing the body, the local environment or the individual cell[7,8]. Because of the fact that the intracellular environment is electronegative compared to the extracellular one, the Pi transit into the cell does not happen by simple diffusion, but is mediated by Na+-coupled Pi cotransporters, which is a regulated event[9]. In addition, Pi is coming out as an essential signalling molecule capable of modifying a lot of cellular functions by varying signal transduction pathways, gene expression and protein levels in many cell types[8,10-12].
It has been shown that high tissue phosphate concentrations increase oxidative stress in endothelial cells[13]. In human vascular smooth muscle cells it has been demonstrated that inorganic phosphate has effects on cell cycle and apoptosis, as well as, in the same cells, the increase of phosphate levels influences cellular and matrix elements promoting calcification[14,15].
Moreover, it has also been supposed that high inorganic phosphate value speeds up senescence process in mouse models[16]. Recent data have confirmed that diets with a high intake of Pi enlarge tumorigenesis in the two-stage skin carcinogenesis model and K-ras lung cancer model in mice[17,18].
In addition, inorganic phosphate has been demonstrated to promote the activation of distinct pathways like ERK1/2 and Akt kinases, as well as it stimulates cell growth in specific cell types, such as preosteoblastic MC3T3-E1 cells, human lung cells, epidermal JB6 cells, proposing Pi as a mitogenic molecule in these cells[17-21].
Recently, a large scale transcriptomics and proteomics research has evidenced that many pro-angiogenic genes and proteins are upregulated by raised Pi levels in preosteoblasts cells[22] as osteopontin (OPN), a secreted cytokine, and forkhead box protein C2 (FOXC2), a forkhead box transcription factor, both proteins recently associated with tumour angiogenesis. Lately, it has been demonstrated that in cancer cells Pi encourages tube formation and endothelial cells migration in vitro if exposed to elevated extracellular Pi levels, with FOXC2 and OPN as possible proteins involved in this mechanism[23].
Notably, the pro-tumors and proliferative effects of Pi are not possible to extend to all cell types, in fact, it has been related that in MO6-G3 odontoblast-like cells Pi induces apoptosis[23,24].
Previously, in the last years, we published a succession of articles, in which the aim has been to study the effects of elevated Pi on human osteosarcoma cell line U2OS and to know possible molecular mechanisms involved[25-28].
Initially, we demonstrated that inorganic phosphate inhibits cell growth and reduces aggressiveness of human osteosarcoma cell line U2OS, identifying adenylate cyclase, beta3 integrin, Rap1, ERK1/2 as proteins whose expression and function are influenced by Pi[25,26].
Later on, we proved also that Pi is capable of increasing the sensibility of osteosarcoma cells to doxorubicin in a p53-dependent manner and through down-regulation of ERK1/2 pathways[27,28].

More recently, we described initial evidence of a strong antiproliferative action of Pi in MDA-MB-231 cell line, an extremely aggressive human triple negative breast cancer model, enlarging the hypothesis of Pi as a novel signalling molecule capable of modifying the function and survival of specific cell types[11].


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As part of our continuing effort to extent the knowledge on the role of inorganic phosphate as a “naturally occurring molecule” acting also as a “sensitizer” to increase the therapeutic index of clinical antitumor drugs, in a current study we describe that Pi induces strongly sensitization to doxorubicin by apoptosis induction in MDA-MB-231. We also show that Pi increases doxorubicin-induced cytotoxicity and that this mechanism involves ERK1/2 and STAT3 down-regulation[29].
It is important to underline that in our studies we use a very low doxorubicin dose (until 0.1 μmol/L) that it is known to be a bearable dose because related to minimal side effects in patients, thus suggesting the possible clinical relevance of this positive pharmacological interaction[30,31].
Latterly, new drug delivery system, called Calcium-phosphate nanoparticles, has been built up. Moreover, it is important to remember that hydroxyapatite nanoparticles release inorganic phosphate and that its retention, most likely, modifies Pi concentration at local sites[32,33].
Furthermore, phosphate is the richest anion in the intracellular environment, with a concentration of 100 mmol/L, so it is easy to find an increase of extracellular Pi as a consequence of cell death induced by chemotherapy.
Maintenance of Pi systemic levels remains a crucial point, because an increase of serum values, even if moderate, and polymorphisms in genes implicated in Pi homeostasis may have effects on ageing process and lifetime[2].
The quantities of inorganic phosphate continue to rise in the diet, in particular way in the western countries, and an increase of the morbidity and mortality in the exposed population has been linked to this habit[3,4].
In Particular, it is known that diet is an environmental element which can be manipulated; it has important consequences on genomics and proteomics functions and it is strongly connected to cancer[34,35].
Inorganic phosphate, as a common dietary element, might modify cells behaviour. However, the possibility that Pi can modify cell functions and its relationship to cancer have to be fully understood and investigated further[36,37].
By the way, the findings that inorganic phosphate, a simple “naturally occurring molecule”, can have antiproliferative actions on some cancer cell types, depending on cell status and genetic background (p53, estrogen receptors, caspases expression, etc.) and can increase cytotoxic effects when combined with doxorubicin, show its potential for clinical applications, suggesting that up-regulating Pi levels at local sites for brief times might contribute to the development of novel and cheap modalities for therapeutic intervention in some tumors, including triple-negative breast cancer and osteosarcoma.
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Conflict-of-interest statement: The authors have no conflict of interests.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: Creative Commons — Attribution-NonCommercial 4.0 International — CC BY-NC 4.0

Peer-review started: May 30, 2015

First decision: July 3, 2015

Article in press: September 30, 2015

P- Reviewer: Agilli M, Higa GM, Jang IS, Yang YS

S- Editor: Tian YL L- Editor: A E- Editor: Li D

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Magnesium Linked To Aging Mystery & Calcifications

By Dr. H. Ray Evers
The average American consumes only 40 percent of the recommended daily allowance of magnesium. This has serious consequences, including death, in many people, according to magnesium expert Dr. Mildred Seelig. Eighty to 90 percent of the U.S. population is magnesium deficient.

Dr. John Prutting said in an issue of "Family Circle" that 70 percent of Americans had mismanaged their diets enough to have some degree of magnesium deficiency.

Magnesium activates 76 percent of the enzymes in the body according to Dr. Sonni Alvarez. Potassium is primarily concerned with the way we use calcium and sodium.

Every doctor knows about the dangers of potassium deficiency, but few recognize that almost half of the patients with a potassium deficiency will also be depleted of magnesium In fact, the low potassium state often cannot be easily corrected unless magnesium is also given.

Most mineral deficiencies stimulate an appetite for the deficient mineral, but there is no "specific appetite" for magnesium Although intravenous magnesium is the drug of choice at the onset of a heart attack, it is not mentioned in the section on arrhythmias in the 1989 "Compendium of Drug Therapy."

Magnesium is useful in preventing unwanted calcification in the kidney, bladder and in the joints.

If a diet is high in phosphorus (common in many meat dishes as lunchmeats, hot dogs, etc. and also in soda drinks), the phosphate binds up the magnesium into magnesium phosphate, which isn't absorbed. Thus, you need more magnesium for complete balance.

In disease and stress states, more magnesium is needed. If a person is using diuretics (water pills), he should make sure his magnesium intake is adequate. Potassium supplementation is usually needed also. The higher the protein you consumer the more magnesium is needed. When large amounts of calcium are consumed, you need more magnesium.

Rabbits just can't take a high-cholesterol diet. Their blood fat level goes up, and they get severe arteriosclerosis/atherosclerosis. However, if you feed them five times the recommended daily allowance of magnesium, their cholesterol goes down and they don't get arteriosclerosis.

Magnesium is a very important ingredient of the green coloring matter in plants (chlorophyll). Magnesium helps in the use of fat in the diet. In many cases of individuals suffering from irritability, the blood has shown low values for magnesium.

Normal development apparently depends on the presence of magnesium. Approximately 70 percent of the magnesium in the body is found in the skeletal system. At least half of the magnesium in the body is combined with calcium and phosphorus in the bones. The remainder is in the muscles, red blood cells and the other tissues of the body.

Magnesium ensures the strength and firmness of the bones, and it makes the teeth harder. Adequate intake of magnesium counteracts acidity, poor circulation and glandular disorders. Children with magnesium deficiency are very often mentally backward.

Influences On Absorption
The absorption of magnesium from the intestines may be influenced by (1) the parathyroid hormone, (2) the condition of the intestines, (3) the rate of water absorption, and (4) the amounts of calcium, phosphate and lactose (milk sugar) in the body.

Recent studies have shown that magnesium deficiency is found in 25 percent of eating disorders, such as obesity and anorexia nervosa. Symptoms such as weakness, leg cramps, anxiety and confusion will often clear up with magnesium therapy. A magnesium deficiency in humans can occur in patients with diabetes, chronic diarrhea or vomiting.

Heart palpitations, "flutters" or racing heart, otherwise called arrhythmias, usually clear up quite dramatically on 500 milligrams of magnesium citrate (or aspartate) once or twice daily or faster if given intravenously.

The optimal daily requirement for children of 20 kilograms of body weight is 0.25 grams (a kilo is 1,000 grams, equal to 2.2046 lbs). A child of 20 kilos would weigh 44.09 lbs, and for an adult of 70 kilos the requirement is 0.35 grams. The recommended daily allowance is approximately 200 to 300 mg for men and 300 mg for women, although specific requirements depend upon body size.

High-Calcium Dangers
A diet which is high in calcium increases the body's need for magnesium and also may increase the excretion of phosphorus and calcium; however, dietary intake of magnesium remains relatively low. The chemical reaction of magnesium is alkaline (acid binding). It regulates the acid-alkaline balance of the body.

Magnesium is one of the nutrients needed to lose weight. Undulant fever is said to clear up if above-adequate amounts of magnesium and manganese are given.

Without sufficient magnesium, one cannot control the adrenals, and this lack of control can result in diabetes, hyperexcitability, nervousness, mental confusion and difficulty coping with simple day-to-day problems. Depressed and suicidal people often display inadequate levels of magnesium.

Magnesium helps induce passage of nutrients in and out of cells and thus affects the life process. It also controls metabolism of proteins, fats, and carbohydrates, resulting in more normal nutritional levels. Japanese investigators have discovered that magnesium will relieve asthmatic attacks. They give it intravenously for acute asthma and orally for prevention.

Human Cell's Power Plant
The power plant of human cell is called the "mitochondrion." The mitochondrion is what generates energy for the cell to use. What everyone refers to as "energy" is derived from the oxidative reduction of the cellular respiration. This is done through the mitochondria.

But the problem arises when the cell is low in magnesium, relative to calcium. Adenosine triphosphate, the "energy currency" of the cell, is magnesium dependent. This means it is obvious that the calcium pump at the cell membrane is also magnesium dependent.

Without enough "biologically available" magnesium, the cellular calcium pump slows down. Thus a vicious cycle is established. The low levels of available magnesium inhibit the generation of energy, and the low levels of energy inhibit the calcium pump.

The end result? The mitochondrion, the powerhouse of the cell and the entire body, becomes calcified. This is the beginning of aging. It all starts in the cell. First the cells age. This leads to organ aging. And after the organs age, individual aging occurs. Since calcium is readily accumulated by mitochondria, this ion is potentially capable of antagonizing the activating influence of magnesium on many intramitochondrial enzyme reactions.

This means that every function of your body can be inhibited when the mitochondria calcify. It's like going through life with the emergency brakes on. Calcium is the brake. Magnesium is the accelerator. To be in optimal health, there must be a balance between the two.

Balance Is Key
Both minerals are vitally important, but there must be that critical balance.

Andre Voisin in his book "Soil, Grass and Cancer" wrote: "Calcium content cannot be considered separately without taking the other mineral elements into account. It is the equilibria, and not the individual elements, that govern the phenomena of life." That's the magic word - "equilibria."

Everyone today is concerned with their chronological age. But they should be equally concerned with their "biological" age. The ratio of calcium to magnesium within your cells is your "biochemical age."

Tragically, in many cases, children are now starting to show high cellular calcium levels. For many people, eating a diet high in calcium and low in magnesium amounts to "cellular suicide."

Calcification can cause a thousand illnesses. As the body grows, the calcium migrates from the hard tissues (bones) to the soft tissues in your body. Few understand the full scope of this program. It is the most prevalent clinical finding in industrial cultures.

Where the calcium buildup occurs depends upon your individual biochemistry. Calcium deposits in the joints are called arthritis; in the blood vessels it is hardening of the arteries; in the heart it is heart disease, and in the brain it is senility.

The calcification process develops slowly. It occurs gradually over 10, 20, 30 years or more. It can begin in childhood. There is almost no soft tissue in your body that is immune from calcification, including your various glands.

All of this fits so well with my basic belief in medicine, which rests upon the word "balance" - mental, spiritual and physical balance. If we have perfect peace of mind and soul and eat a nutritional poison-free diet, we will have no disease, because, after all, each of us in a scientific sense, is a chemical factory.