Selenium and α-Difluromethylornthine in Combination have Strong Activity Against Elevated Polyamines and Glucose Levels in Serum
Mohammed A. Al-Omair
In the present study mice were supplemented with 2%
of both L-arginine and L-ornithine in drinking water for four weeks. L-arginine
and L-ornithine intake elevate polyamine levels in serum of female Swiss
albino mice. The effect of selenium (Se) administration (as sodium selenite:
0.5 or 1 mg kg-1 body weight) or/and Î±- difluromethylornthine
(DFMO: 2 mg kg-1 body weight) on the elevated polyamine levels
was studied. The elevated polyamine levels were decreased significantly
by administration of low and high doses of Se with DFMO. Glucose concentration
in the serum increased significantly with high polyamine level of groups
and reduced back around the normal values by Se and DFMO treatment. The
concentrations of triglycerides and cholesterol are not effected by the
elevated levels of polyamines in the serum. These results suggest that
administration of Se in combination with DFMO protect cells from the harmful
effect of high levels of polyamines.
Polyamines such as spermidine, spermine and their precursor, putrescine are
extensively distributed in nature and display a variety of important biological
activities (Blagbrough et al., 1997). These compounds
influence DNA replication and translation, protein synthesis, membrane stabilization
and the activity of certain kinases and topoisomerases. Charge neutralization
of intracellular DNA and RNA may be among the most important physiological roles
of these compounds. Stabilization of precise DNA conformations may be significant
for nucleosome arrangement, chromatin condensation and gene expression (D`
Agostino et al., 2005; Tabor and Tabor, 1999;
In mammalian cells, polyamines are synthesized from L-arginine to L-ornithine
using arginase in extrahepatic tissues (MÃ©ndez,
1995). Ornithine is then decaboxylated into putrescine by the action of
ornithine decarboxylase enzyme (ODC, EC 4. 1.1.17) (Ramya
et al., 2006; McCann and Pegg, 1992; Heby,
1981). ODC is the primary and rate restrictive enzyme in polyamine biosynthesis.
Increased ODC activity are parallel to levels of polyamines generally be increasing
the proliferating cells such as those live in embryos and cancer cells (Krause
et al., 2000; Pegg et al., 1987). Therefore,
inhibition of ODC activity might stimulate the reduction of intracellular polyamines,
which an effective anticancer cure plans.
Alpha-Difluromethylornthine (DFMO) is an ornithine analogue that inhibits ODC
enzyme activity irreversibly (Manni et al., 2007;
Metcalf et al., 1978). In the presence of both
ODC and DFMO a transitional carbonic species is generated from the decarboxylation
development to DFMO by an enzymatic system. With the loss of fluorine the transitional
carbonic species alkylates a nucleophlic residue in nearby at the active site,
resulting in covalent binding of inhibitor to the enzyme (Metcalf et al.,
1978). Therefore, DFMO has been established to be considerably repressing many
cancer formations (Meyskens and Gerner, 1999).
Selenium is an indispensable trace element in the nutrition for humans and
other animals and is necessary for the development of mammalian cells in way
of life (Zeng, 2002). Sodium selenate has insulin like
effects in vitro in fat cells which causes the translocation of glucose
transporters to the plasma membrane (Ezaki, 1990). The
metabolic basis of this nutritional purpose remained unclear, however, until
it was identified that the enzyme glutathione peroxidase posses Se as a vital
element in its catalytic center (Rotruck et al., 1973).
The proteins which include Se in its structure, such as, glutathione peroxidases
and thioredoxin reductases, are important antioxidant and detoxification agents
(Ganther, 1999). The relation between polyamines biosynthesis
and Se metabolism is that both of them required S- adenosylmethionene as a cofactor
(Kajander et al., 1990).
Putrescine and spermidine are necessary for in vitro insulin and protein
biosynthesis, whereas spermine depletion affects numerous processes implicated
in insulin metabolism. It is usually agreed that glucose is the most important
control device of the insulin gene (Welsh, 1989). This
nutrient is thought to enhance insulin mRNA contents both in vitro and
in vivo and increases of as much as 10-fold have been observed on glucose
stimulation (Brunstedt and Chan, 1982). The glucose consequence
is mediated by a combination of enlarged transcription of the insulin gene and
a careful stabilization of insulin mRNA against degradation (Welsh
et al., 1985). The stimulatory effect of glucose on insulin-gene
transcription may, in part, be mediated by cyclic AMP (Nielsen
et al., 1985). It has been shown that other nutrients also improve
insulin-gene expression (Welsh et al., 1986) and
that the insulin mRNA contents often correlate well with the rate of islet ATP
creation (Spinas et al., 1987; Eizirik
et al., 1988).
The aim of present research was to study the effects of Se and/ or DFMO
on the high levels of polyamine and glucose levels of induced in the serum
of experimental mice utilizing both L-arginine and L-ornithine.
MATERIALS AND METHODS
All the chemicals used were AR grade and obtained from Sigma chemical
Co and BDH chemicals LTD.
DFMO dosing solution was dissolved in deionized water and delivered
in 0.2 mL. Sodium selenite (Na2SeO3) was prepared
with the required amount in deionized water and stored at 4 Â°C. DFMO
and sodium selenite were administered individually once daily by intraperitonealy
Female Swiss albino mice (kindly provided by Veterinary Research Centre
and Animal Production, King Faisal University, Saudi Arabia) at 6 weeks
of age, 24 Â± 2 g body weight (b.wt.). They were permitted free
admission to feed a standard diet and water with a 12 h light/ dark cycle
at controlled temperature.
Study Groups and Sampling
Polyamines levels in the experimental mice were elevated by adding together
both L- arginine (2%) and L-ornithine (2%) in the drinking water for 4 weeks
according to the method described by Teixeira et al.
(2002). The mice were randomly distributed into seven groups (each group
n = 8), housed separately in stainless steel cages.
||Received water free of any chemical additives
||Received L-arginine (2%) and L-ornithine (2%) in drinking water
||As group 2 and received seven doses of DFMO (2 mg kg-1
b.wt.) by ip injection
||As group 2 and received seven doses of Se (0.5 mg kg-1
b.wt.) by ip injection
||As group 2 and received seven doses of both Se (0.5 mg kg-1
b.wt.) and DFMO (2 mg kg-1 b.wt.) by ip injection
||As group 2 and received seven doses of Se (1 mg kg-1
b.wt.) by ip injection
||As group 2 and received seven doses of both Se (1 mg kg-1
b.wt.) and DFMO (2 mg kg-1 b.wt.) by ip injection
The experimental animals were anesthetized and blood samples were
collected. The blood samples were centrifuged at 3000 rpm for 10 min.
Serum samples were collected for biochemical parameter determinations.
Estimation of Glucose
Glucose concentration in the serum was measured. In this method glucose
is oxidized by glucose-oxidase to gluconic acid and hydrogen peroxide,
followed by the reaction of hydrogen peroxide with 4-aminophenazone and
phenol, catalyzed by phenol oxidase to produce a complex dye that is registered
Estimation of Cholesterol
Cholesterol concentration was measured in the serum by cholesterol
oxidase. The total cholesterol concentration is proportional to the dye
product formed by the reaction of hydrogen peroxide released with the
4-aminophenazone and phenol reagent, measured at 540nm.
Estimation of Triglycerides
Triglyceride levels were determined in the serum. This method is based
in the triglyceride hydrolysis by lipase and the glycerol formed is utilized
by glycerol kinase, phosphoglycerol oxidase and peroxidase to form hydrogen
peroxide, which reacts with 4-aminophenazone and phenol to produce a complex
that is measured at 620nm.
Aliquots of serum were extracted with 0.6 N perchloric acid for 1 h at 4
Â°C prior to centrifuge at 10000 rpm for 15 min. The supernatant was used
for polyamine determination. The polyamine levels were determined using high-pressure
liquid chromatography as described by Manni et al.
(2002). The concentration of polyamines was determined by graphical analysis
relative to that obtained from a standard curve generated for each polyamine.
All the values are represented as Mean Â± SD (n = 8). Studentâ€™s
t-test was applied to calculate the significance of difference between
groups. The level of significance was set at p < 0.05.
Effect of L- Arginine and L- Ornithine Supplementation
Arginine is a substrate for ornithine biosynthesis and the ornithine
is the originator of the polyamines. Therefore, the consequence of addition
of 2% L-arginine and 2% L-ornithine on the polyamines synthesis were demonstrated.
Body weights of mice treated with L-arginine and L-ornithine were not
significantly affected in all studied groups in the experiment. The levels
of putrescine, spermidine and spermine in the serum of group 1 (not treated
with L-arginine or L-ornithine) were increased significantly (p < 0.001)
from 3.67 Â± 0.53, 3.22 Â± 0.61 and 2.63 Â± 0.23 to
6.05 Â± 0.42, 4.39 Â± 0. 44 and 3.34 Â± 0.11, respectively
compared to the serum values in the same order (Table 1).
These results indicate that the addition of both L-arginine and L-ornithine
to the drinking water of the experimental animals can cause a significant
elevation in the polyamine levels in serum.
Effect of Se or/and DFMO on the Elevated Polyamine Levels
The supplementation of experimental animals with 0.5 mg Se kg-1
body weight (Table 1, group 4) reduce the elevated level
of putrescine in serum by 14.2%. Also, high Se dose 1 mg kg-1
body weight (Table 1, group 6) decrease the putrescine
level in serum by 32.2%. Group 2 was considered as a control. As represented
in Table 1, group 4 low Se dose reduced the spermidine
level in serum by 12.8%. Moreover, the high Se dose (Table
1, group 6) depleted the spermidine level in serum by 22.3%. The spermine
level in serum was decreased by 3.6% with low Se dose and 15.6% with high
As represented in Table 1, group 3 the DFMO abolished
both the putrescine levels in serum by 77.4% and the spermidine level
by 62.2 %. On the other hand, the DFMO increase the spermine level 22.5%
in serum. The combination between both Se and DFMO tend to normalize the
polyamine levels in the serum.
Glucose, Triglycerides and Cholesterol Levels in Serum
The supplementations with 2% L-arginine and 2% L-ornithine increased
the glucose levels in the serum of group 2 significantly (p < 0.05)
compared to untreated control group 1. Se or DFMO caused depletion in
the elevated glucose concentrations as represented in Table
2. Se and DFMO administrations interperitoneally tended to normalize
the elevated serum glucose levels (Table 2).
The triglyceride levels in the serum did not change greatly and no differences
were observed between the various experimental groups except group 3 that
treated with DFMO which declined the triglyceride level by 20.4% than
the control group (Table 2). Also, the levels of cholesterol
in serum revealed no significant differences between the various experimental
mice groups (Table 2).
|| Level of polyamines such as putrescine, spermidine
and spermine in serum of the control and experimental mice
|| Levels of glucose, TG and TC in serum of the experimental
In the present study polyamines and glucose concentrations increased significantly
with supplementation of both L-arginine and L-ornithine in the drinking water
of the experimental mice. L-Arginine and L-ornithine, as a target for consumption
of arginase activity, are essential for the synthesis of polyamines (Wu
and Morris, 1998). Arginase activity is linked to cell development and connective
tissue formation, which is connected with polyamines, proline and in ammonia
detoxification. Many reports stated that arginine starvation greatly decreases
putrescine, spermidine and spermine contents in the rate (Schertel
and Eichler, 1991) mice (Teixeira et al., 2002).
Polyamines levels inside the cells are firmly synchronized and can be altered
through the putrescine, spermidine and spermine biosynthesis and interconversation,
particularly ornithine decarboxylase (Ackermann et al.,
2003), that quickly responds to a number of stimuli and are largely linked
with cell growth (Wallace et al., 2003; Thomas
and Thomas, 2001).
In ordinary tissues ODC action is enlarged by a multiplicity of ecological
and hereditary factors linked with carcinogenesis, including ultraviolet light
and carcinogenic agents. Increased ODC activity persists and is associated with
a wide variety of epithelial neoplasms including skin, breast, prostate, colon,
(Gerner and Meyskens, 2004). Polyamines and ODC are increased
in breast cancer corresponding to regular breast tissue. The enlarge of polyamines
levels are correlated with a less differentiated and more metastatic tumor phenotype
(Glikman et al., 1987; Canizares
et al., 1999). Increased polyamine synthesis has been associated
with proliferation and progression of breast cancer and thus, is a potential
target for anticancer therapy (Satriano et al., 1998).
Polyamine depletion by DFMO has been shown to decrease pulmonary and bone metastasis
from human breast cancer cell (McCann and Pegg, 1992;
Davidson et al., 1999).
The toxic dose of DFMO is 200 and 135 mg kg-1 in rats and rabbits,
respectively (Kirchner et al., 1999). In the present
study we utilized 2 mg DMFO kg-1 body weight of the experimental
mice. DFMO inhibits putrescine and spermidine and increases the level of spermine,
these results are in agreement with the results of Jun et
al.(2007) and Halline et al. (1989).
The results in the present study indicates that the elevated polyamines
levels can be modulated with combination of both Se and DFMO.
Battell et al. (1998) applied very high selenium
doses over 2 mg kg-1 i.e., close to the LD50, which are
equal to 3.5 mg kg-1 body weight per day to achieve decreased blood
glucose level. In the present study we applied low dose of Se (0.5 mg kg-1)
and high dose of Se (1 mg kg-1) body weight. Selenium supplementation
has in recent times been shown to decrease total cancer incidence. The results
indicts that the elevated polyamine levels can be modulated with combination
of both Se and DFMO. However, the mechanism of action of selenium as an anticarcinogenic
agent has yet to be elucidated (Redman et al., 1998).
Earlier studies in animals and humans have shown that selenium compounds can
prevent cancer development. The results suggest that selenium is able to reduce
the risk for liver cancer even when it is used only during a short period of
time covering the promotion phase of the carcinogenic process. Chemically induced
hepatocarcinogenesis may be prevented by selenium supplementation both during
promotion and progression phase (Bergman et al., 2005).
Present results are in agreement with the results of Battell
et al. (1998) in that Se compounds induce decrease in the blood glucose
level. Elevated blood glucose levels was reduced 50- 80% following Se administration
to type I diabetic rats. Se action in high polyamine levels seems to result
from reversal of abnormal hepatic expression of glycogenic, gluconeogenic and
lipogenic enzymes, particularly glucokinase, pyruvate kinase and glucose 6-
phosphate dehydrogenase (Stapleton, 2000). Polyamine cations exist at millimolar
concentration in panceriatic Î² cells.
In the present study the glucose concentration increased in the elevated polyamine
levels and we utilized DFMO and Se to attenuate the glucose induced in the elevated
polyamines levels. DFMO specifically and irreversibly inhibits the ODC enzyme
that present in the Î²-cells which lead to depletion of putrescine and spermidine
(Eiziriket et al., 1988). Very little is known
about the effect of both Se and DFMO on the elevated levels of amines poly.
In the present study, we have examined whether Se or DFMO or both play a role
in polyamine and glucose regulations. In agreement with present results Ramya
et al. (2006) reported that the elevated polyamine levels by L arginine
and L ornithine did not change the triglycerides or cholesterol levels in serum
but increase the glucose concentration in blood.
L-arginine and L-ornithine inhibit glucose oxidation and had no effect
on the lipolysis in serum. Although no direct measurements of glucose
transport have been conducted the results of a series of experiments indicate
that Se and DFMO similar to insulin which facilitate glucose transport
in cells. The extent to which insulin and polyamines share a common pathway
of action was further studied by evaluating the interaction between spermidine
and the insulin receptor site. The relationship between the structures
of the polyamines and their insulin-like properties does not, at present,
provide any clear insight concerning the mechanism of action of these
compounds. Similar structural requirements may occur for the stabilizing
effects of polyamines on glucose transport.
The glucose-induced increase the synthesis of insulin mRNA and total RNA remained
unchanged in islets treated with DFMO, suggesting that the glucose effect was
not mediated by increased spermidine. However, the finding that insulin mRNA
levels did not increase, when the glucose-induced rise in both polyamines was
prevented, implicates spermine alone, or the combination of spermine and spermidine,
as a possible mediator of parts of the glucose effect. It is unlikely that Se
in addition to DFMO exerted a general and non-specific effect on the islet RNA
(Eizirik et al., 1988) metabolism, since the rates
of total RNA synthesis and turnover were not affected by the inhibitors.
The present experiments demonstrate that L-arginine and L ornithine increase
blood glucose level. The protective action of polyamines on Î²-cells
was demonstrated, as well as the capability of these compounds to accelerate
their replication when they were damaged by alloxan administration. L-arginine
and spermidine inhibited hemoglobin glycation and lipid peroxidation in
diabetic animal models. The precise mechanism by which L-arginine and
spermidine act is still obscure.
In conclusion, present study showed that inhibition of polyamins biosynthesis
with DFMO markedly suppressed tumor cells.
The financial support by the Deanship of Scientific Research (Project
No. 6021) King Faisal University, Saudi Arabia is gratefully acknowledged.
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