Polyamines, cancer and chronic pain: what links?

Polyamines, cancer and chronic pain, therapeutic tracks still little explored

 

Behind this technical term lies a family of molecules essential to life. Primarily three in number – putrescine, spermidine, spermine – they are closely involved in cell division and proliferation processes. Some studies thus highlight their potential links in the development of cancer and more recently in the management of chronic pain.

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What are polyamines?

First discovered in the 17th century in human seminal fluid, their recognition as essential molecules for cellular metabolism is relatively recent. Polyamines are low molecular weight molecules that cause strong electrostatic interaction with other molecules. By allowing in particular to initiate the synthesis of DNA and proteins, polyamines are thus closely related to the growth processes of cells, including cancer cells. The origin of polyamines is primarily food and from the intestinal flora, although the body can also make. Under normal physiological conditions, the diet is able to cover the needs:

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Polyamines and cancer

Several studies show that cancer cell proliferation is dependent on polyamine levels and that there are higher concentrations in cancer cells compared to normal cells, or that there are relationships between polyamine metabolism and cancers. digestive, breast or prostate. In animals, the combination of a chemotherapy treatment with a diet without polyamines has doubled the survival time and significantly reduced metastatic pulmonary dissemination. In humans, a study was conducted in 13 patients with metastatic prostate adenocarcinoma. A diet reduced in polyamines for six months 5 days out of 7 was proposed to them, in parallel with an intestinal decontamination:

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Polyamines and chronic pain

According to a study conducted by Pr Breivik’s team in 2006, 15 to 32% of French people suffer from chronic pain. Pain is a complex and multidimensional manifestation based on a process that is certainly neurobiological, but also influenced by emotions, memory and automatisms. The sensitivity to pain can thus be modulated in a negative way to reduce the sensitivity (process on which many analgesic drugs are based), but also in a positive way according to a less known process causing an increase in sensitivity. to pain. This last mechanism could not only explain the differences in perception or resistance to pain depending on the individual, but also the appearance of chronic pain in pathologies such as fibromyalgia or neuropathic pain. By preventing the hyperfunctioning of certain receptors (NMDA) by a negative modulation mechanism, it could then be possible to reduce the perception of pain while respecting the physiological functioning involved, unlike certain drugs traditionally used. It is precisely at this level that the properties of the polyamines are highlighted. A study conducted by Prof. Simonnet and his team has shown that a diet low in polyamines could be proposed to significantly prevent both the long-term pain induced by inflammation or lesion and the hypersensitivity to pain. Such a diet could also,

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Controlled supply of polyamines

The proposal of a polyamine controlled content diet represents an innovative nutritional approach, it can indeed be particularly interesting to optimize the effectiveness of conventional treatments. The roles of food in the prevention and support of certain pathologies are more and more highlighted, the example of polyamines is significant. The use of such a diet may, however, raise questions because of the exclusion of certain foods normally considered to be beneficial to health, but this is a specific protocol, the possible benefits of which may justify its temporary application without questioning the long-term interests of foods that are rich in polyamines.

Main foods to avoid in the context of a diet low in polyamines (the polyamine contents are here correlated to the size of the portions conventionally consumed):

  • Citrus fruits and their juices, grapes and their juice, mangoes, lychees, bananas, passion fruit,
  • Peas (all families), lentils, beans, green peppers, tomatoes, mushrooms, sauerkraut,
  • Whole spelled, buckwheat and rye flour and their derivatives, oatmeal, soya (excluding milk and yogurt), quinoa, seeds (flax, sesame, squash, sunflower), hazelnuts ,
  • Certain cheeses (Cantal, Comté, Brie, Munster, Reblochon, Roquefort, Auvergne blue),
  • The liver and its derivatives, seafood, soy sauces and Tempeh.

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Roles of polyamines

Discovered for the first time in the seventeenth century in the human seminal fluid, their recognition as essential molecules to cellular metabolism, and no longer as a simple product of degradation, is relatively recent. It only dates from the 1950s. Polyamines are molecules of low molecular weight, consisting of a carbon chain having at least two amino groups positively charged at physiological pH. By making it possible in particular to initiate the synthesis of DNA and proteins, the polyamines are thus closely related to the growth processes of the cells. Their level is, moreover, higher in proliferating cells compared with quiescent cells. An intracellular depletion of polyamines is also responsible for the induction of apoptosis. Spermine, because of its large number of positive charges, is also the polyamine with the strongest activity and plays a specific role in the structural organization and reactivity of chromatin. In particular, it is capable of protecting the DNA from the action of the endonucleases responsible for DNA fragmentation, which enzymes are induced during the execution phase of apoptosis.

Discovered for the first time in the seventeenth century in the human seminal fluid, their recognition as essential molecules to cellular metabolism, and no longer as a simple product of degradation, is relatively recent. It only dates from the 1950s (1,2) . Polyamines are molecules of low molecular weight, consisting of a carbon chain having at least two amino groups positively charged at physiological pH. Their properties lie largely in the existence of these positive charges, causing a close electrostatic interaction with other macromolecules loaded negatively: DNA, RNA, ATP, proteins or membrane phospholipids.By making it possible in particular to initiate the synthesis of DNA and proteins, the polyamines are thus closely related to the growth processes of the cells. Their level is, moreover, higher in proliferating cells compared with quiescent cells (3) . Intracellular depletion of polyamines is also responsible for the induction of apoptosis (4) . Spermine, because of its large number of positive charges, is also the polyamine with the strongest activity (5,6) and plays a specific role in the structural organization and reactivity of chromatin (7).. In particular, it is able to protect DNA from the action of endonucleases responsible for DNA fragmentation, enzymes that are induced during the apoptosis execution phase (8, 9) .

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Source of polyamines

Like the complexity of cell function, the metabolism of polyamines is dependent on many factors. Their origin is multiple: they can come from an endogenous synthesis, the food and the intestinal flora.

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1) Endogenous synthesis

 Endogenous synthesis involves four enzymes: ODC (ornithine decarboxylase), S-adenosylmethionine decarboxylase (SAM-DC), spermidine and spermine synthetase. There are also several retroconversion pathways for the regeneration of putrescine and spermidine. Polyamines are synthesized by most cells, but are also derived from dead cells and exogenous sources transported by a specific system, the STP, ensuring the regulation of intracellular levels.  ODC is a key enzyme strongly involved in polyamine regulatory metabolism. The gene coding for this enzyme is also considered a pro-oncogene it is indeed a gene present in all cells but overexpressed in tumor cells and whose product is involved in proliferation and malignant transformation (10, 11) .

 Diagram 1

Catros-Quemener V. Polyamines: diagnostic role and therapeutic target in oncology (58)

2) Dietary intake of polyamines

Under normal physiological conditions, the diet is able to cover the polyamine requirements, thus avoiding a de novo synthesis (12-19)  : dietary intakes are estimated between 300 to 600 μmol per day depending on the country (17- 19) , the amount of polyamines in the diet depends on the nature of the foods eaten, but also on their degree of fermentation (15) , their method of preparation and cooking (16) . Thus, the determination of the amounts of polyamines present in the food remains difficult to establish and depends on the methods of analysis used (20) or the nature of the polyamine considered (21).. In simplified terms and in relation to the quantities consumed per portion, the foods richest in polyamines are:

  • Citrus juices (orange, grapefruit), grape juice and mango (or multifruits)
  • Chickpeas, split peas, beans, peas, soy (excluding soya milk), lentils, pumpkin seeds, flax, sesame and sunflower , the spelled flour, buckwheat and whole rye and their derivatives (pasta, bread, etc.) , quinoa, oatmeal, kidney beans, pistachios, peanuts, corn, soya steaks, quinoa flower bread,
  • Certain unpeeled and unpeeled fruits and vegetables  : orange, pear, pomelo, queen-claude, lychee , banana, mushrooms, clementine, passion fruit, broccoli, cauliflower , Romanesco cabbage, eggplant, zucchini , watercress, spinach, green peppers, soy sprouts (mung beans), cherry tomatoes, sauerkraut, gherkins.
  • Some cheeses: Cantal, Comté, Brie, Munster, Reblochon, Roquefort, Auvergne blue
  • The liver, pork, duck, pigeon, guinea fowl, pheasant, kidneys, rosette, liver pate, foie gras , oysters, mussels, scallops, clams, liver cod, periwinkles, whelks, salmon eggs,
  • Condiments and herbs: carrot or mustard shoots, wheat germ, baker’s yeast, spirulina, oat bran pickles, pollen, Tamari sauce, soy sauce, Tempeh, basil, chervil, oregano, turmeric, curry, garlic powder, saffron.

A number of foods considered to be beneficial to health, particularly because of their richness in antioxidants and plant active ingredients (citrus fruits, legumes, pollen, turmeric or broccoli for example), appear here rich in polyamines. The implementation of a nutritional protocol to reduce polyamine intake is carried out in a specific context (accompanying chemotherapy treatments or chronic pain) and can therefore justify the reduction or temporary exclusion of these foods. In the specific case of turmeric, its total polyamine content (between 218 and 591 nmol / g according to the analyzes and origins) makes it a food that can be maintained at a moderate dose given the small quantities consumed per serving (a few grams).

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3) Production by the intestinal flora

The intestinal flora is composed of about 100,000 billion bacteria, belonging to various genera, species and families. The nature of the flora depends on many factors, including the type of bacteria implanted in the first months of life of the infant and diet (22) . In general, flora bacteria produce large amounts of polyamines from protein waste, especially spermidine, although the proportions may vary depending on the type of bacteria (23,24). The diet itself therefore influences the production of polyamines by the microbiota: depending on the nature of the food consumed, certain strains of bacteria will have substrates that promote their growth. An insufficiently chewed diet rich in protein will favor, for example, the proliferation of a so-called putrefaction flora, at the origin of an increased production of amines.

The cells of the intestinal mucosa are particularly involved in the metabolism of polyamines. They are indeed both exposed to food sources and polyamines from the intestinal flora itself (25). The ingestion of exogenous polyamines, in particular spermine, seems to be related to the maturation of the digestive system in the rat. Indeed, several arguments link this phenomenon to the introduction of spermine in the diet: the inhibition of ornithine decarboxylase delays the establishment of an adult type of intestinal phenotype, the amount of spermine ingested via the diet increases considerably at weaning, the maintenance of newborns in a polyamine-depleted diet delays the normal development of the intestinal mucosa, the oral administration of spermine induces early postnatal development of the small intestine and human pathologies characterized by delayed intestinal development are considered to be related to polyamine deficiency(26) .

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What are the relationships between polyamines and cancer?

As we mentioned earlier, polyamines are closely involved in neoplastic cell proliferation processes (3, 27-30) . Two researchers at the University of Rennes, Pr Moulinoux and Simonnet, have particularly studied the relationships that may exist between polyamines and cancer (31) . Several in vitro studies have shown that cancerous cell proliferation is dependent on polyamine levels, particularly through the regulation of ODC and that there are higher concentrations in cancer cells compared to normal cells (28). -31). There is indeed an increase in de novo synthesis and intracellular absorption of polyamines within tumor cells (1, 25, 32) . The question of the association between the induction of ODC, the intracellular accumulation of polyamines and tumor cell growth is therefore legitimate and has been the subject of numerous studies on different cancers (33) . Carcinogens cause a transient increase in ODC whereas its inhibition reduces cell growth and transformation (1, 27, 33, 34) . Similarly, overexpression of the ODC gene allows cells to acquire angiogenic abilities (35). The metabolism of polyamines is therefore a potential marker of the proliferative cancer level(53,54) and the target for antiproliferative drugs (1,36) . Several studies have shown relationships between the metabolism of polyamines and digestive, breast or prostate cancers (37-43) . Moreover, in patients with metastatic prostate adenocarcinoma, erythrocyte polyamine levels correlate with tumor progression (44,45).. In animals, the level of circulating polyamines represents one of the essential parameters for the proliferation of tumor cells. Tumor tissue captures extracellular polyamines more and polyamine deficiency promotes the antiproliferative effect of anticancer drugs while reducing their toxicity (46). The combination of an inhibitor of ODC, Neomycin © , and Flagyl ©, as well as a diet devoid of polyamines has doubled the survival time of animals and significantly reduce metastatic pulmonary dissemination. Finally, the combination of a low polyamine diet with an intestinal decontamination without a polyamine biosynthesis inhibitor results in a 50% decrease in tumor growth in the prostate (46).. A study was conducted in 13 patients with metastatic prostate adenocarcinoma. A diet containing reduced polyamine content for 6 months 5 days out of 7 was proposed to them, in parallel with intermittent intestinal decontamination with neomycin and metronidazole: the results showed an improvement of the general state according to the WHO score, a significant pain-relieving effect with a decrease in analgesic consumption, an absence of hepatic toxicity as well as a return of pain and a deterioration of the general state following cessation of the diet (47, 48) .

diagram 3

Catros-Quemener V. Polyamines: diagnostic role and therapeutic target in oncology (58)

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Involvement of polyamines in pain

According to a study conducted by Pr Breivik’s team in 2006, 15 to 32% of French people suffer from chronic pain (49) . The IASP (Taxonomy Committee of the International Association for the Study of Pain) defines pain as “an unpleasant, sensory and emotional experience associated with present or potential tissue damage or described in these terms” . Pain is therefore a complex and multidimensional manifestation based on a process that is certainly neurobiological, but also influenced by emotions, memory and automatisms.

At the peripheral level, the pain is indeed caused by the stimulation of nociceptive receptors located especially at the mucocutaneous level. This stimulus will then be transformed into the electrochemical potential generated by the ion exchange, to reach the level of the posterior horn of the spinal cord, more precisely the convergence neuron, which will process the information to transmit it to the hypothalamus. The hypothalamus is also the place of treatment for other external factors, including emotions and experiences, which will potentially modulate the perception of pain. The nervous system is also able to reduce its own sensitivity to pain via endogenous opioid systems. It is also according to this principle of negative modulation, or of hyposensitivity to pain, that many antalgic drugs are developed. Conversely,there are less known, so-called positive modulation processes, which lead to an increase in pain sensitivity: these mechanisms could not only explain the differences in perception or pain resistance depending on the individual, but also the appearance of chronic pain (50-54) .

 

Repeated or high doses of opioid analgesics may cause latent hypersensitivity to pain (54-56), felt to be stronger and more enduring than the original stimulation itself. This hypersensitivity can then give rise to a pain sensation triggered by a non-sensory stimulus (non-nociceptive environmental stress or SEEN). Thus, animals that have already been confronted with an opioid or an injury despite the fact that the latter is cured, may suffer from a pain all the more exacerbated that this stress will be repeated. This point is particularly interesting: it highlights the fact that the effectiveness of a drug on an individual can vary depending on the experience of this individual. Moreover, more animals undergo repeated non-nociceptive stress,Extrapolated to humans, this mechanism highlights how the history of the stress of an individual is important to understand the reactions of the latter to pain and opens new avenues for reflection on the possible origins of pain described as exaggerated such as fibromyalgia or neuropathic pain.

 schema 4

Simonnet Guy: Nutritional Approach to Pain (57)

A new approach to managing chronic pain

 The pain sensitization processes are dependent on NMDA (N-methyl-D aspartate) receptors via the intervention of excitatory amino acids such as glutamate and aspartate. With each nociceptive stimulus, the NMDA receptors are indeed activated and thus participate in the amplification of the pain. Indeed, the NMDA receptors have polyamine reception sites that can modulate their action. Via a mechanism of double inhibition (the activation of the polyamine receptor sites induces the inhibition of another proton-sensitive receptor site, itself inhibiting the functioning of NMDA receptors), the presence of polyamines could give rise to stimulation. positive for NMDA receptors and conversely, the absence of polyamines could reduce the hyperfunctioning of these receptors and the sensitivity to pain that results. A study conducted by Prof. Simonnet and his team has shown that a diet low in polyamines could be proposed to significantly prevent both the long-term pain induced by inflammation or lesion and the hypersensitivity to pain. Such a diet could also, as a curative this time, significantly reduce chronic pain, including in case of low sensitivity to the action of morphine and without the side effects induced by NMDA antagonists. as long-lasting pain induced in case of inflammation or injury as the hypersensitivity to pain. Such a diet could also, as a curative this time, significantly reduce chronic pain, including in case of low sensitivity to the action of morphine and without the side effects induced by NMDA antagonists. as long-lasting pain induced in case of inflammation or injury as the hypersensitivity to pain. Such a diet could also, as a curative this time, significantly reduce chronic pain, including in case of low sensitivity to the action of morphine and without the side effects induced by NMDA antagonists.

Pain sensitization processes are dependent on NMDA (N-methyl-D aspartate) receptors via the intervention of excitatory amino acids such as glutamate and aspartate (52, 53) . With each nociceptive stimulus, the NMDA receptors are indeed activated and thus participate in the amplification of the pain. By preventing their hyperfunctioning by a negative modulation mechanism, it could then be possible to reduce the perception of pain while respecting the physiological functioning involved, unlike certain drugs traditionally used. It is precisely at this level that the properties of the polyamines are highlighted.Indeed, the NMDA receptors have polyamine reception sites that can modulate their action. Via a mechanism of double inhibition (the activation of the polyamine receptor sites induces the inhibition of another proton-sensitive receptor site, itself inhibiting the functioning of NMDA receptors), the presence of polyamines could cause stimulation. NMDA receptors and, conversely, the absence of polyamines could reduce the hyperfunctioning of these receptors and the sensitivity to pain that results. A study conducted by Prof. Simonnet and his team has shown that a diet low in polyamines could be proposed to significantly prevent both the long-term pain induced by inflammation or lesion and the hypersensitivity to pain.(57) .

 

The proposal for a controlled polyamine diet is an innovative nutritional approach. It can indeed be particularly interesting to optimize the effectiveness of conventional treatments. As a reminder, once the quantities correlated to the size of the portions conventionally consumed, the main foods to avoid in this context are  :

  • Citrus fruits and their juices, grape juice and its juice, mango, lychees, banana, passion fruit,
  • Peas (all families), lentils, beans, green peppers, tomatoes, mushrooms, sauerkraut,
  • Whole spelled, buckwheat and rye flour and their derivatives, oatmeal, soya (excluding milk and yogurt), quinoa, seeds (flax, sesame, squash, sunflower), hazelnuts ,
  • Certain cheeses (Cantal, Comté, Brie, Munster, Reblochon, Roquefort, Auvergne blue),
  • The liver and its derivatives, seafood, soy sauces and Tempeh.

 

The roles of food in the prevention and support of certain pathologies are more and more highlighted, the example of polyamines is a significant one. The use of such a diet may, however, raise questions because of the exclusion of certain foods usually considered generally beneficial to health, but here again is a specific protocol, the possible benefits of which may justify its temporary application without questioning the interests of food, which is rich in polyamines over the long term.

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