Magnesium Disturbances by Carcinogenesis
During chemical carcinogenesis it is possible to observe Mg cellular deficit in preneoplastic and neoplastic states. Mg deficit causes structural and functional alterations of the plasma membrane with a decrease of the intracellular cations Mg and K and an increase of the extracellular cations Ca and Na in neoplastic cells. These drastic changes are grossly similar to the cellular alterations observed in magnesium deficiency. One of the principles for the prophylactic use of Mg in oncology is to avoid the facilitation of the effect of a carcinogenic agent by the induction of cellular disturbances of this type. In fact, the disorders in magnesium distribution in carcinogenesis are far more complex than those observed in simple Mg deficiency. During the neoplastic state, Mg bound in intracellular structures decreases for the most part while its concentration in the cytosol and sometimes in mitochondria increases. This type of disturbance in Mg distribution, unobserved in simple Mg deficiency, indicates an alteration of the intracellular Mg regulation, i.e., a type of Mg depletion even at an early stage of carcinogenesis. At a later stage, disturbances in Mg distribution are even more complex. In man, at a later cancerous stage, the disturbance in Mg distribution associates an increased Mg level in the tumor and in blood cells including erythrocytes and lymphocytes, with some stigmata of Mg depletion which differ according to the clinical type and treatment. For example, the Mg level of breast cyst fluids does not constitute a risk indicator for breast cancer. A high concordance exists between high Mg/Ca ratio levels in meningiomas and the absence of microscopic calcifications, which may testify to the inhibitory potency of Mg against mineralization. Mg depletion appears more frequently in patients with solid tumor malignancy than with hemopathic malignancy. Radiation enteritis increases fecal Mg loss and cancer cachexia urinary Mg loss in particular. Mg depletion does not occur equally in all tissues. Experimental and clinical data show that usually the adverse effect of Mg depletion in nonneoplastic tissue are reversible.
Recent advances concerning the systemic interaction between Mg and cancer rely on the close and complex links between Mg and the immune system. The anticarcinogenic action of Mg rests of Mg stimulation of cancer immunosurveillance and inhibition of immunofacilitation. Reverse mechanisms concern the carcinogenic effects of Mg deficit. The paths are either humoral or cellular.
Mg stimulates synthesis of cytotoxic antibodies. Simultaneously its activation of an alternative pathway of complement increases their inhibiting effect on tumor growth. Mg-dependent immune tumor cytolysis is mediated by blood monocytes, mainly by T lymphocytes, and by polymorphonuclear neutrophils with a mechanism of tumor cell injury due to activated oxygen. Nonimmune antitumor surveillance mediated by natural killers also requires Mg2+ for target cell lysis.
Study of immune disturbances of Mg deficiency shows the reverse mechanisms of cancer immunosurveillance inhibition and allows better identification of the type of T cytolytic lymphocyte concerned. The percentage of total T lymphocyte and that of T lymphocyte with helper function are reduced whereas the percentage of T lymphocyte with suppressor function is enhanced. Futhermore, Mg deficit induces an oncogenic inflammatory reaction with an increase of phlogistic glycoprotein, leukotriene B4, and superoxide anion. Lastly, the same low responsiveness of histamine releasers is similarly noted in spleen cells of rat with experimental Mg deficiency and in rat basophilic leukemia cells. These immune data and those concerning nonimmune natural killers are consistent with some anticancer properties of Mg.
Immune Carcinogenic Actions of Mg and Anticarcinogenic Action of Mg Deficit
Among the major features in cancer immunosurveillance and in experimental and clinical magnesium deficiency, hyperhistaminemia and histamine hyperreceptivity appear to be similarly important. Part of the anticarcinogenic action of Mg deficit may be compared with clinical improvement observed in some advanced cancer diseases after a treatment combining histamine and H2 antihistaminics. This mechanism does not exclude a hypothetical increased level of the tumor necrosis factor in blood nor an inhibition of the immunofacilitation due to the immune carcinogenic actions of Mg. Mg may stimulate synthesis of antibodies and of T lymphocytes which induce tumor growth..
These data are relevant to some antitumor effects of magnesium deficit. It seems interesting to emphasize a number of similarities between the effects of hyperproduction of cachectin and those observed in a Mg-deficient state. Both situations associate pro- and anticancer factors. Both reduce activity of lipoprotein lipase and blood pressure, may lead to disseminated intravascular coagulation, induce an imflammatory reaction with an increased level of leukotrienes, similarly alter membrane permeability, activate polymorphonuclear leukocytes, and lastly protect mice from lethal inoculum of malarial plasmodium. It is therefore tempting to speculate regarding the hypothesis of a hypersecretion of "cachectin tumor necrosis factor" during magnesium deficit.
Immunostimulation and immunosuppression may be either useful or noxious in cancer treatment. The beneficial or detrimental effects of Mg load and Mg deficit agree with this notion. But, in fact, hemolymphoreticular malignancies are usually under immunosurveillance: in such cases the Mg stimulating effects are useful. However, most often solid tumors are immunostimulated. It is therefore advisable to be careful with all types of immunostimulation and particularly with Mg treatment. This rule admits some exceptions, e.g., the control of a badly tolerated Mg deficit, especially when it is induced by a side effect of an efficient cytolytic treatment like cis-Pt.
Magnesium and Anticancer Agents
In recent studies the relationship between Mg and two anticancer metals, i.e., gallium (GA) and cisplatin (Cis-Pt), has been observed. Ga and Cis-P5 decrease the ionic permeability through the human amnion, estimated by the measurement of the total ionic conductance (Gt) on the two sides (maternal and fetal), except that Cis-Pt already does this at low concentration on the fetal side. There is a noncompetitive inhibition between Mg and Ga, i.e., Mg and Ga are fixed on different sites on the surface membrane.
Moreover, there is no antagonism between Mg and Cis-Pt.
Selenium, a metalloid, may be considered with regard to its anticancer properties. The Se-mediated anticarcinogenesis seems to be due to an action on glutathione, and this action is identical to the effects observed in the case of magnesium deficiency1. In the human amnion, Se decreases Gt on the maternal side, but has no effect on the fetal side. There is a noncompetitive antagonism between Mg and Se on the maternal side; Mg and Se are fixed on different sites on the surface membrane.
The reduction of the membrane conductance Gt, a deleterious effect, observed in these data indicates that the anticarcinogenic effects of Ga, Cis-Pt, and Se are located on targets other than the plasmatic membrane. The noncompetitive antagonism (Mg-Ga, Mg-Se) and the absence of action (Mg-Cis-Pt) may indicate that the sites of anticancer agents and Mg are localized in another part of the cell (Cis-Pt may control the Mg level on N7 of guanine in DNA, for example) if their antitumoral effects are due to competitive actions of Mg.
Magnesium and Anticancer Antibiotic
Mithramycin is an antitumor antibiotic that can basically be considered to have powerful properties of the same type as calcitonin. Mithramycin can in fact cause a rapid and severe lowering of the blood magnesium level.
In the human amnion, mithramycin reduces Gt on the maternal side but has no effect on the fetal side. There is no antagonism between Mg and mithramycin. These results limit the role of the membrane in the effects of mithramycin.
Jean Durlach, Michel Bara and Andrée Guiet-Bara;