Download Magnesium, calcium and cancer

Magnesium Research 2009; 22 (4): 247-55
REVIEW ARTICLE
Magnesium, calcium and cancer
Leopoldo J. Anghileri
Retired Director of Research, Medicine Faculty, University Henri-Poincaré-Nancy 1, Nancy,
France
doi: 10.1684/mrh.2009.0173
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Correspondence: Dr L.J. Anghileri, 95 rue de Marèville, 54520 Laxou, France
<[email protected]>
Abstract. Magnesium ion (Mg2+) and calcium ion (Ca2+) control a diverse and
important range of cellular processes, such as gene transcription, cell proliferation, neoplastic transformation, immune response and therapeutic treatment.
Their characteristic biologic antagonism makes it important to treat the most
important aspects of that competitive behavior together. This synopsis aims to be
a useful means of promoting further research on the relationship between both
cations and human health affected by environmental conditions.
Key words: magnesium, calcium, cancer, magnesium/calcium ratio, carcinogenesis
An exceptional, complete and concise description
of the biological properties of magnesium, related to
the human health, was published in 1985 [1]. This
brief review has for aim to present an evaluation
of the most important experimental publications
concerning the subject. The extraordinary evolution
of the technology, and the consequent creation of
ecologic problems, emphasizes the importance of a
better knowledge of the interactions between magnesium and calcium, so relevant to biological equilibrium in health and in illness. The purpose of this
review is to provide the references from research
work performed in different specialized biologic
fields where Mg2+ and Ca2+ have an important
involvement.
Magnesium and calcium cellular activity
Magnesium is involved in energy metabolism, in
nerve impulse transmission, in muscle contraction,
and in bone mineralization. It forms complexes with
ATP, ADP and GTP, being necessary for the activity
of enzymes implicated in the transfer of phosphate
groups such as gluco-kinase, phosphofructo-kinase,
phosphoglycerate-kinase, pyruvate-kinase, DNApolymerase, ribonucleases, adenylcyclase, phosphodiesterases,
guanilate-cyclase,
ATPases
and
GTPases [2]. It is intercalated, by electrostatic
bonds, between two oxygen atoms, each one carrying a negative charge resulting from its ionization.
The compartmentalization of Mg2+ within the cell is
a key element in coordinated control by regulation
of pathways in which the rate-limiting steps are
transphosphorylation reactions [3]. Mg2+ has a role
in the regulation of protein synthesis and protein
synthesis is very sensitive to small changes of intracellular Mg2+ within physiological ranges and the
onset of DNA synthesis is dependent on the rate
of protein synthesis [4-7]. Both Mg2+ and Ca2+ are
implicated in rather similar biochemical processes
that regulate the metabolism and the reproduction
of the eukaryotic cell [8]. Mg2+ binds to sites of fundamental importance to chromosome structure and
is implicated in its metabolism, because it is a necessary cofactor for DNA synthesis and without it
DNA synthesis is hindered and cellular division is
stopped [9].
The cells have a system of signals, channels, and
a large family of Ca2+-binding effector proteins
which produce and relay the Ca2+-signals that start
and coordinate a vast array of cellular functions and
even gene transformations. Cell-cycle transit and
differentiation can change dramatically along the
different stages of carcinogenesis. Depending upon
the physiological environment, there are cases in
which the roles of Mg2+ and Ca2+ are antagonistic
to each other. Calcium antagonists and their mode
of action were described in 1986 [10]. Mg2+ effects
on the cell plasma membrane are shown by its competition with Ca2+ from the CaATP molecule, its
activation as MgATP of both the Ca2+-pump and the
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L.J. ANGHILERI
Na+-pump, and for the exchange of Na+ against K+
because the Na/K ATPase protein needs Mg2+ and
PO43- ions. In this way, Mg2+ is responsible for the
functioning of the transmembrane mechanism that
maintains the gradients of Na+ and K+ [11]. At
physiological levels Mg2+ is not genotoxic, but it is
highly required to keep genomic stability [12].
Magnesium and calcium in carcinogenesis
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Carcinogenesis is a multistage and a multifactorimplicated process in which Mg2+ plays an important role. Besides being involved in biochemical
reactions that are crucial to cell proliferation, angiogenesis and apoptosis, another of its important
effects is its influence on the biological responses of
immuno-inflammatory cells. A first step of carcinogenesis is the interaction of the carcinogenic factor
with the plasma membrane of the cell, followed by
the essential condition of oncogene-induction, further evolution of which leads to the neoplasia.
There are different types of carcinogenic agents:
organic chemicals, radiation, viruses and heredity
factors. The oncogene is the result of a process of
changing the DNA in some of the cells, and these
cells, by a subsequent action of promoters that
enhance the formation and development of abnormal cells, result in the formation of a malignant
transformation (tumor). The oncogene derives
from a protooncogene that encode proteins of regulation of cell growth and differentiation. The protooncogene to oncogene transformation occurs by a
gene mutation or an increased expression level.
The characteristics of the plasma membrane are
changed to initiate the carcinogenesis process.
There is a drastic change in ionic flux from the
outer and inner cell membranes in the impaired
membranes of cancer, as is also observed in magnesium deficiency. The transport of ions is dependent
on both the concentration gradient of the ion and
the electric potential across the membrane, which
is affected by the membrane surface charge [13,
14]. The thioacetamide intoxication and hepatocarcinogenesis produced by its prolonged feeding to
animals have appeared as a progressive phenomenon in which morphological changes were associated with important biochemical modifications.
Changes in the permeability of plasma cell membrane induce an indiscriminate in- and outflux of
extra- and intracellular cations, and produce an
increased Ca2+ intracellular accumulation with a
consequent injury of the mitochondria by
Ca2+-overload. The cell membrane permeability
248
change appears to be produced by modifications
in the phospholipid metabolism, as shown by
increased incorporation of radioactive phosphorus
into the acidic phospholipids: phosphatidyl ethanolamine and phosphatidyl serine [15]. Compared with
control animals, the affected tissues, the hepatoma
and the cholangiocarcinoma induced by thioacetamide, the hepatoma and the cholangiocarcinoma
induced by 4-dimethylaminoazobenzene, presented
increased Ca2+ and Na+, whereas Mg2+ and K+
were decreased [16]. A study with eight different
types of transplanted tumors in animals showed
that the Mg/Ca ratio increases sharply with the
tumor growth and after reaching a maximum, it
decreases as the tumor grows further. The increase
is sharp in fast growing tumors and more gradual in
slow growing ones. The higher growth rate with an
increase in Mg2+ concentration was considered as
an implication of Mg2+ in the high metabolic activity
of the tumor [17]. Concerning tumor growth, Mg2+
deficiency has been reported to inhibit primary
tumor growth but to favor metastasis in mice; this
is a paradoxical behavior that depends on Mg2+ status [18, 19].
Calcium signalling, magnesium-calcium
antagonism and magnesium to calcium ratio
Calcium ions play a significant role in a great variety
of cellular activities acting as a second messenger in
Ca2+-signalling. The signalling system is based on
the generation of brief pulses of Ca2+ resulting
from the coordinated release of Ca2+ from internal
stores using either inositol 1,4,5-triphosphate or ryanodine receptors [20], and different types of cells
using components selected from an array of signalling homeostatic and sensory mechanisms [21]. The
effects of Mg2+ are generally opposite to those of
Ca2+, it has a Ca2+ antagonist effect, shown by inhibition of Ca2+ receptor- and voltage dependent
channels [22]. In this way it protects mitochondria
against calcium overload [23], an effect that appears
related to the mitochondrial permeability transition
pore, and to the mitochondrial transmembrane
potential.
The ratio of magnesium to calcium is very important in relation to the causes and prevention of a
number of disorders, such as myocardial infarction
or arrhythmia, atherosclerosis, hypertension, urolitiasis, and infant-death syndrome. A higher Mg/Ca
ratio is desirable because of the beneficial role of
Mg2+. The same type of Mg/Ca ratio is required in
the case of carcinogenesis which is a multistage and
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MAGNESIUM, CALCIUM AND CANCER
multifactor process, in which Mg2+ plays an important role that is the well known effects of Mg2+ deficiency and supplementary therapy.
Extracellular Ca2+ influx, induced by trivalent
metal ions (Fe3+, Al3+, In3+, La3+ and Ga3+), is
enhanced by the ATP ligand that inhibits the polymerization of the solvated cation taking place at
physiological pH. This consequently permits its biological activity; thus the lack of correlation between
lipid peroxidation and increased Ca2+ uptake has
been demonstrated [24]. This Ca2+ accumulation is
not specific for tumors and also takes place in other
pathological states such as experimental calciphylaxis, tissue inflammation and infectious focus,
where the metabolism of both Mg2+ and Ca2+ is
locally modified. This interpretation of the phenomenon is also valid for the cations already mentioned
which are implicated in isomorphous ionic replacement [25]. The La3+ acts in a different way to that of
a calcium antagonist because it inhibits the calciumATPase cell pump, by stopping its protein in a phosphorylated form and thus blocking the transition
from the first form of the protein to the second
form, which performs ATP hydrolysis [26]. Another
type of process is shown by Mg2+. It influences the
CaATPase and the Na/K ATPase functions by shifting the relation of the pump towards exchange.
Mg2+ competes with Ca2+ from the CaATPase, and
Mg2+ as MgATPase activates both the Ca-pump and
the Na-pump [27]. The concentration of Mg2+ stimulates the phosphorylation of the Ca-pump protein of
the sarcoplasmic reticulum by inorganic phosphate,
but this effect is reversed by a high Mg2+ concentration. There are two conformational forms of the
enzyme: E1 and E2. The former is the form of
enzyme that presents two high-affinity Ca2+ binding
sites, and it is phosphorylated by ATP when Ca2+ is
bound. Mg2+ is weakly-bound in the two Ca2+ binding sites and to a third site, known to be present on
F1, with the result of stabilization of F1 at the
expense of F2, particularly when the Mg2+ concentration is high. This stabilization of F1, at pH 6.2 and
25°C, is a highly cooperative function of Mg2+ concentration and appears not prevented by increased
phosphate concentration [28].
An experimental series of studies using Ico OFI
(IOPS, Caw) mice, bearing genetically induced lymphoma genes, have permitted to verify the role of
Ca2+-signalling induced by iron complexed by ATP
acting as Ca2+ signal activation agent. In comparison with untreated lymphomagene-bearing control
mice, the iron and ATP-treated showed a reduction
of life span (or survival), as well as a lack of the
characteristic accumulation of a substantial volume
of ascites. These results are an index of the degree
of malignancy of the induced lymphoma and their
relationship with the increased intracellular calcium
homeostasis changes. Spleen and liver, which are
the target organs besides the lymph nodes, showed,
with respect to the control animals, a generally
lower pattern of Mg2+ distribution, whereas the
values in solid tumor-bearing animals were very
high, as in the tumor [29]. When the treatments
were done by percutaneous, subcutaneous and
intraperitoneal administration, both ATP compounds induced a generalized lymphoadenitis,
which, in the case of FeATP, led to solid lymphomas. The effects in any case were more important
in the injection area, apparently due to an immediate interaction of the Ca2+ signal with the oncogenes [30]. It is very important to note that in all
these experiments the Mg2+ concentrations of the
animals dead before 9 months were lower than in
the control group. This observation indicates a
direct relationship between carcinogenesis evolution and Mg2+ deficiency.
The implication of Mg2+ in normal and pathological cellular physiology is a well known phenomenon
[31-38]. Small changes in Mg2+ levels may have
important effects on cardiac excitability and on vascular tone. Accordingly, Mg2+ may be important in
the regulation of blood pressure, and perturbations
in cellular Mg2+ homeostasis could play a role in
pathophysiological processes underlying blood
pressure elevation [39]. Altered cellular physiology
occurs
after
acute
exposure
to
severe
Mg2+deficiency, whereas long-term exposure to a
moderate deficiency was found to accelerate cellular senescence. These observations suggest that
chronic Mg2+ deficiency may be a promoter of agerelated diseases [40]. A study on common iliac arteries with aging demonstrated that the magnesium to
calcium ratios were higher at an early stage of the
accumulation of calcium and phosphorus in the
arteries than at an advanced stage of the accumulation [41]. Moderate dietary Mg2+ deprivation results
in calcium retention and altered potassium and
phosphorus excretion [42]. A high Mg2+ consumption is linked to a significantly lower risk of colorectal adenoma, particularly for subjects with a high
Mg2+:Ca2+ intake [43]. The increased calcium/magnesium ratio in cells from hypertensive animals is
a pathogenetic factor for the development of arteriosclerosis and hypertension [44]. Extracellular
Mg2+ regulates nuclear and perinuclear free Ca2+
in cerebral vascular smooth muscle cells that
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L.J. ANGHILERI
indicates the possible implication of hypomagnesemia on cerebral-central nervous system pathobiology, and, particularly on alcohol provoked strokes
[45].
Synergism in carcinogenesis
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Using the animal model of mice bearing genetically
induced lymphoma genes, the complex and
multifactor-determined evolution of carcinogenesis
has been investigated [46]. The evaluation of accumulated experimental results on the action of iron
provoking cell injury, indicates that it is rather the
consequence of an inhibition of the cytosolic Ca2+
concentration regulatory system than an effect of
iron-induced lipid peroxidation on cells. After parenteral iron administration of iron, complemented
by determination of the in vivo uptake of
59
Fe-labeled ferric gluconate and ferric-ATP complex, the results of mortality, clinical and histopathological examination have demonstrated a
synergism between radiofrequency and ferric gluconate, and the increased risk of radiofrequency exposure, when it is simultaneous to parenteral iron
administration [47]. These results corroborate the
importance of the pathological evolution of iron
overload to a neoplasia that has been presented as
statistical evidence [48], and by the induction of sarcomas at the site of parenteral administration of
iron dextran in animals as well as in humans [49,
50]. A similar study of the synergism in the system
Al3+-radiofrequency, showed an early mortality
increase in concomitance with lymphoid element
proliferations and infiltration of the liver and spleen
[51], supporting the concept of Al3+ competition
with Mg2+, implicated in the inhibition of the buffering and extruding extracellular Ca2+ system [52].
Mg2+ is one of the cations most affected by Al3+
interference, its function, more than any other cation, is affected by competition with Al3+ [53], and
size similarity is a dominant factor over the charge
identity concerning metal ion competition [54, 55].
Gallium in cancer diagnosis and therapy
The mechanism of accumulation of the widely used
diagnostic agent 67Ga-citrate can be interpreted by
means of the isomorphous replacement model. The
in vitro ATPase inhibition by Ga3+ appears to be the
result of the ionic replacement of Mg2+ by Ga3+.
This replacement may be the main cause of radioactive Ga3+ accumulation by tissues: a similar ionic
radius for Mg2+ = 0.65 Å than Ga3+ = 0.62 Å, but a
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higher valence for Ga3+ makes a competitive binding of Ga3+ by Na,K- Mg2+-dependent ATPase possible [56]. It is interesting to note that this ionic
replacement is also valid for iron-binding sites
because the Fe3+ ionic radius is equal to 0.64A°
[57]. The factors affecting 67Ga accumulation have
been well pointed out in an extended review [58].
Ribonucleotide reductase controls the balance of
the deoxyribonucleotide pools, and changes in its
activity can alter the mutation of cells [59]. Augmented ribonucleotide activity has been associated
with disease states including cancer [60, 61]. Inhibition of DNA synthesis by gallium is probably due to
a combination of a block in iron availability to ribonucleotide reductase and a direct inhibition of the
enzyme by gallium [62]. This could explain why gallium nitrate has been used in cancer chemotherapy
[62, 63].
Hyperthermic treatment of cancer
In hyperthermic treatment of experimental tumors
submitted in vivo to hyperthermia, done in the presence, or not, of La3+, modifications in the concentration of extra- and intracellular cations have been
shown. Sacrificed immediately after hyperthermia,
only the group treated with La3+ presented ionic
changes: lower Mg2+ and K+. After 48 hours, in
both cases, Ca2+ and Na+ were increased while
Mg2+ and K+ were decreased [64]. These changes
in the ionic composition: increased Ca2+ and
decreased K+ concentration, and the additional
decrease in ATP concentration, appear as an effect
of the hyperthermic inhibition of the ATPdependent extrusion mechanisms of the cell which
induces ionic environmental modifications [65].
Differences in membrane fluidity may account for
differences of thermal sensitivity. To increase the
cytotoxicity of tumor cells at hyperthermia temperatures, a variety of chemotherapeutic agents have
been tested. The increase of Ca2+-uptake by tumor
cells during hyperthermia appears linked to a failure
of the Ca2+-pump in relation to an inhibition of
Ca-ATPase [66], and this alteration of the ATPase
system might be related to changes in ATP concentration during hyperthermia, as demonstrated by
31
P-nuclear magnetic resonance spectroscopy [67].
The changes in membrane fluidity maybe implicated
when, in infarct from permanent middle cerebral
artery occlusion in the rat, Mg2+ (as MgSO4) is a
neuroprotective when combined with mild hypothermia, even when the treatment is delayed by several hours [68]. La3+ potentates hyperthermia [69].
MAGNESIUM, CALCIUM AND CANCER
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Magnesium and immune response
Mg2+, besides being involved in biochemical reactions that are crucial to cell proliferation, angiogenesis and apoptosis, shows that one of its important
effects is its influence on the response of immunoinflammatory cells, as showed by Mg2+ deficiency in
cardiovascular diseases that present changes in the
leucocyte subpopulations, which are concomitant
with the cardiopathic lesion progression [70].
Tumor growth needs suppression and/or evasion
of the host immune system, and immune modulation is considered a way to counter and suppress
tumor growth [71-73]. Mg2+ is involved in both carcinogenesis and immune response [74] and it is
important to the immune system in both non specific and specific immune responses, innate and
acquired immune responses [75, 76]. Abnormal
Ca2+-handling induced by low extracellular in vivo
Mg2+ may be at the origin of exacerbated inflammatory responses. It has been suggested that the activation of immune cells is an early event in Mg2+
deficiency [77, 80]. Lymphocyte proliferation is triggered by pulses of increased cellular Ca2+ provoked
by ATP, an effect that is transient and controlled by
the Ca2+-buffering system of the cell, in which Mg2+
is implicated [81].
The differences between Mg/Ca ratios in: control
OFI (Oncine France, Souche 1) mice (a), treated with
NaATP (b), and treated with FeATP complex (c)
were as follows: in the spleen a = 0.67 < b = 1.29 <
c = 1.40, and in the liver, a = 0.55 < c = 0.58 <
b = 1.90. These values agree with the structural
hypertrophy by lymphocyte infiltration and pathologic ascites formation and lymphocytic leukemia
manifestations observed in both organs [47]. These
differences in correlation with the histopathological
observations indicate the role of Mg2+ in both activation of the immune response and in the oncogene
evolution leading to a neoplastic development.
The importance of balanced Mg2+ homeostasis and
the interaction with the immune system is demonstrated. Both in animal models and in human systems, Mg2+ is involved in inflammation, apoptosis
and thymocyte gene expression [78]. During Mg2+
deficiency there are altered cell growth, modifications of ion fluxes and oxidative stress. The observation of the induction of genes involved in the
protection and repair in cells from Mg2+-deficient animals is evidence of the role of oxidative stress in the
pathobiology of Mg2+ deficiency [79, 80]. On the
other hand, several experimental and epidemiological studies have shown an inverse correlation
between Mg2+ status and the risk of some cancers,
but the relationship between Mg2+ and cancer is complex. In mice, an Mg2+-deficient diet retards primary
tumor growth (up to 70%), but Mg2+-repletion in these
mice increases the primary tumor burden [19].
Radiation, magnesium, calcium and cancer
The mitochondrial production of ATP depends on the
nuclear spin and magnetic moment of Mg2+ ion in
creatine kinase and ATPase, as a consequence of it,
the enzymatic synthesis of ATP is an ion-radical process depending on the external magnetic field and
microwave fields that control the spin states of ionradical pairs and influence the ATP synthesis [81, 82].
Studies have consistently shown an increased
risk for childhood leukemia associated with electromagnetic fields [83] and concern is growing about
possible pathologic effects on humans due to exposure to electric and magnetic fields [84]. Numerous
epidemiological studies have demonstrated an
association between cancer and exposure to electromagnetic fields [85]. Not all types of electromagnetic radiation are in fact cancerigens. Low energy
waves on the electromagnetic spectrum generally
are not. Higher energy radiation, including ultra violet radiation, X rays and gamma radiation, are cancerigens when acting in sufficient doses. Chronic
exposure to low doses could be much more harmful
than short-term high doses because of lipid peroxidation initiated by free radicals. The cell membranes and cellular organelles are the main targets
for free radical attacks. Peroxidation of cell membrane increases with a decreasing dose rate (Peticau effect). Gamma radiation results in damage to
the plasma membrane of resting lymphocytes via
the generation of high reactive free radical species.
This damage is reflected in a rapid increase in
plasma membrane permeability and chromosomal
instability and the DNA damage induced may be a
cause of permanent genetic damage. Ionizing radiation is an activator of oncogenes, and an inactivator
of tumor-suppressor genes. Oncogen activation
promotes cellular proliferation that is removed by
the intervention of tumor suppressors. Under long
exposure conditions, radiofrequency (RF) signals at
an average SAR of at least 5.0 W/kg are capable of
inducing chromosomal damage in human lymphocytes [86]. Mediated Ca2+ signalling processes are
involved in electromagnetic field effects on the
immune system [87]. An increase in the Ca2+ influx
appears to be responsible for the effects of
50 Hz electromagnetic fields on voltage-gated-Ca2+
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L.J. ANGHILERI
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channels modulating neuroendocrine cell proliferation and apoptosis [88]. Nanosecond pulsed electric
fields, like ligand-mediated responses, release Ca2+
from internal calcium pools and activate plasma
membrane Ca2+ influxes through its channels or
capacitative Ca2+ entry [89]. The lymphatic system
plays a major role in the immune system defending
against cancer induced by modulated electromagnetic radiation [90], and assessing occupational
exposure risk to microwave radiation [91].
The importance of the effects of RF on the
increased Ca2+ signal responsible for the acceleration of carcinogenesis in animals bearing genetically
produced lymphogenes is a fundamental argument
for the cancer risk from RF exposure [92]. Nanomolar Ca2+ influx induces lymphocyte proliferation and
this RF exposure is a possible factor of disruption,
by variations in the equilibrium existing between
ions, polyanionic macromolecules and glycoproteins of the cell surface, that can be induced by
the rhythmic modulation of the RF. Consequently,
an extracellular Ca2+-influx by passive diffusion
can produce pulses of Ca2+-signal which induce
lymphoid element proliferation. The effects upon
the blood-brain barrier and upon tumor growth in
the mammalian brain appear to support this disruption of cell membrane explanation [93]. On the
other hand, the absence of increased lipid peroxidation in tissues of RF-treated mice corroborates the
independence of the intracellular calcium homeostasis changes from the oxidative stress [45]. On
the other hand, the observed synergism of iron
and aluminium, two elements capable of modifying
cell Ca2+ homeostasis [46, 50], is another factor
implicated in the cancer effects of this type of radiation that corroborates that independence from oxidative stress. This lack of oxidative stress has been
demonstrated by other authors [94]. The use of the
FeATP complex to evaluate the risk of accelerated
carcinogenesis by RF [95] emphasizes the role of
the Ca2+ signal influx in the acceleration of oncogenes and the failure of thymus-determined immune
defences. In addition to this, the presence of genetically inherited factors or those induced by carcinogenics (chemical or physical) is an indispensable
condition for the inherent cancer risk of low energy
level RF radiation [96].
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