Metabolic changes during development of Walker-256 carcinosarcoma resistance to doxorubicin
Aim: To study indices of energy metabolism, content of K+ and Mg++ both in peripheral blood and in Walker-256 carcinosarcoma during development of resistance to doxorubicin. Methods: Resistance of Walker-256 carcinosarcoma to doxorubicin has been developed through 12 subsequent transplantations of t...
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nasplib_isofts_kiev_ua-123456789-1454492025-02-23T19:59:07Z Metabolic changes during development of Walker-256 carcinosarcoma resistance to doxorubicin Todor, I.N. Lukianova, N.Yu. Shvets, Yu.V. Lozovska, Yu.V. Chekhun, V.F. Original contributions Aim: To study indices of energy metabolism, content of K+ and Mg++ both in peripheral blood and in Walker-256 carcinosarcoma during development of resistance to doxorubicin. Methods: Resistance of Walker-256 carcinosarcoma to doxorubicin has been developed through 12 subsequent transplantations of tumor after the chemotherapy. Parental strain was inhibited by drug by 65%, while transitional resistant substrains — by 30% and 2%, respectively. Determination of biochemical indices in blood serum and homogenates of tumor tissue, level of potassium, magnesium, lactate, glucose, activities of lactate dehydrogenase and glucose-6-phosphate dehydrogenase was performed with the help of biochemical and immune-enzyme analyzer GBG ChemWell 2990 (USA) using standard kits. Polarography was used to determine indices of mitochondrial oxidative phosphorylation. Study of mitochondrial membrane potential was carried out on flow cytometer Beckman Coulter Epics XL using dye JC-1. Results: It has been determined that development of drug resistance causes the decrease of K+, Mg++, glucose content in blood serum and increase of these indices in tumor tissue. At the same time, gradual tumor’s loss of sensitivity is characterized by decrease of glycolysis activity in it and activation of mitochondrial oxidative phosphorylation and pentose phosphate pathway of glucose degradation, which causes more intensive formation of NADPH. Conclusion: Development of drug resistance of tumor causes certain metabolic changes in organism and tumor. Further study of such changes will make possible to determine tumor and extratumor markers of resistance. Key Words: tumor, drug resistance, potassium, magnesium, glycolysis, pentose phosphate cycle, mitochondrial membrane potential. 2015 Article Metabolic changes during development of Walker-256 carcinosarcoma resistance to doxorubicin / I.N. Todor, N.Yu. Lukianova, Yu.V. Shvets, Yu.V. Lozovska, V.F. Chekhun // Experimental Oncology. — 2015. — Т. 37, № 1. — С. 19-22. — Бібліогр.: 19 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/145449 en Experimental Oncology application/pdf Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Original contributions Original contributions |
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Original contributions Original contributions Todor, I.N. Lukianova, N.Yu. Shvets, Yu.V. Lozovska, Yu.V. Chekhun, V.F. Metabolic changes during development of Walker-256 carcinosarcoma resistance to doxorubicin Experimental Oncology |
| description |
Aim: To study indices of energy metabolism, content of K+ and Mg++ both in peripheral blood and in Walker-256 carcinosarcoma during development of resistance to doxorubicin. Methods: Resistance of Walker-256 carcinosarcoma to doxorubicin has been developed through 12 subsequent transplantations of tumor after the chemotherapy. Parental strain was inhibited by drug by 65%, while transitional resistant substrains — by 30% and 2%, respectively. Determination of biochemical indices in blood serum and homogenates of tumor tissue, level of potassium, magnesium, lactate, glucose, activities of lactate dehydrogenase and glucose-6-phosphate dehydrogenase was performed with the help of biochemical and immune-enzyme analyzer GBG ChemWell 2990 (USA) using standard kits. Polarography was used to determine indices of mitochondrial oxidative phosphorylation. Study of mitochondrial membrane potential was carried out on flow cytometer Beckman Coulter Epics XL using dye JC-1. Results: It has been determined that development of drug resistance causes the decrease of K+, Mg++, glucose content in blood serum and increase of these indices in tumor tissue. At the same time, gradual tumor’s loss of sensitivity is characterized by decrease of glycolysis activity in it and activation of mitochondrial oxidative phosphorylation and pentose phosphate pathway of glucose degradation, which causes more intensive formation of NADPH. Conclusion: Development of drug resistance of tumor causes certain metabolic changes in organism and tumor. Further study of such changes will make possible to determine tumor and extratumor markers of resistance. Key Words: tumor, drug resistance, potassium, magnesium, glycolysis, pentose phosphate cycle, mitochondrial membrane potential. |
| format |
Article |
| author |
Todor, I.N. Lukianova, N.Yu. Shvets, Yu.V. Lozovska, Yu.V. Chekhun, V.F. |
| author_facet |
Todor, I.N. Lukianova, N.Yu. Shvets, Yu.V. Lozovska, Yu.V. Chekhun, V.F. |
| author_sort |
Todor, I.N. |
| title |
Metabolic changes during development of Walker-256 carcinosarcoma resistance to doxorubicin |
| title_short |
Metabolic changes during development of Walker-256 carcinosarcoma resistance to doxorubicin |
| title_full |
Metabolic changes during development of Walker-256 carcinosarcoma resistance to doxorubicin |
| title_fullStr |
Metabolic changes during development of Walker-256 carcinosarcoma resistance to doxorubicin |
| title_full_unstemmed |
Metabolic changes during development of Walker-256 carcinosarcoma resistance to doxorubicin |
| title_sort |
metabolic changes during development of walker-256 carcinosarcoma resistance to doxorubicin |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2015 |
| topic_facet |
Original contributions |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/145449 |
| citation_txt |
Metabolic changes during development of Walker-256 carcinosarcoma resistance to doxorubicin / I.N. Todor, N.Yu. Lukianova, Yu.V. Shvets, Yu.V. Lozovska, V.F. Chekhun // Experimental Oncology. — 2015. — Т. 37, № 1. — С. 19-22. — Бібліогр.: 19 назв. — англ. |
| series |
Experimental Oncology |
| work_keys_str_mv |
AT todorin metabolicchangesduringdevelopmentofwalker256carcinosarcomaresistancetodoxorubicin AT lukianovanyu metabolicchangesduringdevelopmentofwalker256carcinosarcomaresistancetodoxorubicin AT shvetsyuv metabolicchangesduringdevelopmentofwalker256carcinosarcomaresistancetodoxorubicin AT lozovskayuv metabolicchangesduringdevelopmentofwalker256carcinosarcomaresistancetodoxorubicin AT chekhunvf metabolicchangesduringdevelopmentofwalker256carcinosarcomaresistancetodoxorubicin |
| first_indexed |
2025-11-24T20:37:45Z |
| last_indexed |
2025-11-24T20:37:45Z |
| _version_ |
1849705538541060096 |
| fulltext |
Experimental Oncology 37, 19–22, 2015 (March) 19
METABOLIC CHANGES DURING DEVELOPMENT
OF WALKER-256 CARCINOSARCOMA RESISTANCE
TO DOXORUBICIN
I.N. Todor*, N.Yu. Lukianova*, Yu.V. Shvets, Yu.V. Lozovska, V.F. Chekhun
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv
03022, Ukraine
Aim: To study indices of energy metabolism, content of K+ and Mg++ both in peripheral blood and in Walker-256 carcinosarcoma
during development of resistance to doxorubicin. Methods: Resistance of Walker-256 carcinosarcoma to doxorubicin has been
developed through 12 subsequent transplantations of tumor after the chemotherapy. Parental strain was inhibited by drug by 65%,
while transitional resistant substrains — by 30% and 2%, respectively. Determination of biochemical indices in blood serum and
homogenates of tumor tissue, level of potassium, magnesium, lactate, glucose, activities of lactate dehydrogenase and glucose-
6-phosphate dehydrogenase was performed with the help of biochemical and immune-enzyme analyzer GBG ChemWell 2990 (USA)
using standard kits. Polarography was used to determine indices of mitochondrial oxidative phosphorylation. Study of mitochon-
drial membrane potential was carried out on flow cytometer Beckman Coulter Epics XL using dye JC-1. Results: It has been de-
termined that development of drug resistance causes the decrease of K+, Mg++, glucose content in blood serum and increase of these
indices in tumor tissue. At the same time, gradual tumor’s loss of sensitivity is characterized by decrease of glycolysis activity
in it and activation of mitochondrial oxidative phosphorylation and pentose phosphate pathway of glucose degradation, which causes
more intensive formation of NADPH. Conclusion: Development of drug resistance of tumor causes certain metabolic changes
in organism and tumor. Further study of such changes will make possible to determine tumor and extratumor markers of resistance.
Key Words: tumor, drug resistance, potassium, magnesium, glycolysis, pentose phosphate cycle, mitochondrial membrane potential.
Study of pathogenesis of malignant neoplasms both
in experimental and clinical observations has a great
theoretical and practical significance. While searching
metabolic differences between normal and tumor cells,
researchers have paid attention first of all to those pro-
cesses, which underlie intensity of growth and division
of cells, and, primarily processes of biosynthesis of nucleic
acids and anaerobic and aerobic degradation of carbo-
hydrates — glycolysis and mitochondrial oxidative phos-
phorylation. At that time, significant changes in important
metabolic systems have been observed in tumor cells
[1–7]. The cause of such changes is the loss by tumor
cell of some regulatory mechanisms, which act on genetic
or metabolic level.
Significant role in metabolism of cells is played by wa-
ter-salt metabolism [8–10]. Properties of cells and their
viability also depend on appropriate ion concentrations.
Consumption of glucose by cells is always accompanied
with transfer of potassium from intercellular liquid inside
cell [9]. In general, biochemical reactions require certain
composition of medium and maintenance of appropriate
water-salt balance both in tumor and in organism. This
issue becomes especially important, when it is spoken
of occurrence and development of drug resistance
of malignant tumors. For this reason, in this work we have
studied important bioenergetics indices, content of K+ and
Mg++ in both peripheral blood and Walker-256 carcinosar-
coma during development of its resistance to doxorubicin.
MATERIALS AND METHODS
Experimental model. In the study, female rats
weighting 120–150 g bred in the vivarium of the R.E. Ka-
vetsky Institute of Experimental Pathology, Oncology and
Radiobiology, NAS of Ukraine (Kyiv, Ukraine), were used.
As experimental model, Walker-256 carcinosarcoma was
chosen. Tumor transplantation was performed by subcu-
taneous injection of 20% Walker-256 carcinosarcoma cell
suspension in the thigh area. Animals were housed as the
control (N1) and experimental (N2) groups (nor less than
10 animals per group). When the volume of tumor reached
0.5 cm3, six doxorubicin (Ebewe, Austria) injections
(1.5 mg/kg daily) were administered to the animals of the
group 2. Then the animals were decapitated under nar-
cosis (Sedazin, Biowet-Pulawy, Poland) according to the
rules of Ethic Committee; tumors were resected, 20%
tumor cell suspension was prepared and transplanted
to the animals from the new control and experimental
groups. Then doxorubicin therapy was performed by the
same schedule. In total, 12 courses of tumor transplanta-
tion/doxorubicin therapy were performed.
All studies have been performed during development
of resistance of Walker-256 carcinosarcoma to doxo-
rubicin. Animals, which underwent removal of tumor
for the study, have not received cytostatic drug directly.
Indices of ionic homeostasis and bioenergetics of pa-
rental Walker-256 carcinosarcoma (inhibition of growth
by doxorubicin has constituted 65.0 ± 5.8%) and resistant
variants of this tumor (inhibition of growth has constituted
30.0 ± 2.7% and 2.1 ± 0.5%, respectively) have been
studied.
Submitted: December 21, 2014.
*Correspondenсе: E-mail: todor_igor@yahoo.com;
Lu_na_u@rambler.ru;
Fax: 38(044)258-16-56
Abbreviations used: ADP — adenosine 5’-diphosphate;
NADP — β-nicotinamide adenine dinucleotide phosphate;
NADPН — β-nicotinamide adenine dinucleotide phosphate reduced;
Δψm — the mitochondrial transmembrane electrochemical gradient.
Exp Oncol 2015
37, 1, 19–22
20 Experimental Oncology 37, 19–22, 2015 (March)
Mitochondria study. Oxidative phosphorylation
indices of tumor cell mitochondria were determined
accor ding [11]. The mitochondrial transmembrane
electrochemical gradient (Δψm) was measured using JC-
1-staining [12].
Analysis of mitochondrial transmembrane poten-
tial. The mitochondrial transmembrane electrochemical
gradient (Δψm) was measured using JC-1. JC-1, a cell
permeable, cationic, lipophilic dye freely crosses the mi-
tochondrial membrane and forms J-aggregates which
fluoresce red; accordingly, viable cells with a normal
mitochondrial membrane potential when stained with
JC-1 exhibit a pronounced orange fluorescence (FL2).
Following an apoptotic stimulus, the resultant decrease
in the mitochondrial membrane potential prevents
JC-1 from entering the mitochondria and remains
as monomers in the cytosol that emits a predominantly
green fluorescence (FL1). Therefore, the ratio of J-ag-
gregates/monomers serves as an effective indicator
of the cellular mitochondrial transmembrane potential,
allowing apoptotic cells to be easily distinguished from
their non-apoptotic counterparts. Briefly, Walker-256 cells
(2.5•105/ml) were stained with JC-1 (7.5 mM in PBS,
10 min, 37 °C). Cells were then acquired in a flow cytometer
on the basis of quadrant plot to distinguish monomers from
J-aggregates. To set the quadrants, cells were treated with
H2O2 (20 mM, 37 °C, 30 min), representative of cells with
depolarized mitochondrial membrane potential. The flow
cytometer “Coulter Epics XL” (Beckman Coulter, USA)
was used in studies.
Determination of biochemical indices
in blood serum and homogenates of tumor tissue
of the Walker-256 carcinosarcoma, level of potassium,
magnesium, lactate, glucose, activities of lactate dehy-
drogenase and glucose-6-phosphate dehydrogenase
has been performed with the help of biochemical and
immune-enzyme analyzer “GBG ChemWell 2990” (GBG,
USA) using standard kits for this equipment.
Statistical processing of the data was performed
by the use of the software Statistica (v. 7.0) and Stu-
dent’s t-criterion. A statistically significant difference was
considered to be present at p < 0.05.
RESULTS AND DISCUSSION
As stated above, the problem of drug resistance of ma-
lignant tumors is one of the most significant in oncology.
For this reason, in our studies we primarily have paid atten-
tion to the processes of glycolysis and oxidative phospho-
rylation, which are the main sources of energy and plastic
material for biosynthetic reactions of cell [13]. On the other
hand, during the development of drug resistance, we have
determined level of some ions, which characterize water-
salt metabolism of cells, both in organism and tumor.
The main biological role of electrolytes consists in their
osmotic action, in maintenance of electrical neutrality
in biological fluids and tissues of organism and in their
impact on enzyme reactions in cells. At the same time,
first of all we have evaluated level of К+ and Mg++ in blood
serum and tumor in the process of induction of doxoru-
bicin resistance of the Walker-256 carcinosarcoma. К+
is one of the key element of water-salt metabolism. Its
level in orga nism significantly increases when malignant
process occurs. Moreover, tumor tissue is also characte-
rized by increased concentration of potassium ions [9].
Magnesium is one of the key cations required for
enzyme reactions [8, 13]. For instance, for the activity
of DNA-polymerase and phosphofructokinase, allosteric
enzyme of glycolysis, ions of Mg++ are highly required.
In general, magnesium is required for reactions with as-
sistance of most of phosphokinases.
In the result of carried out studies, the following data
concerning concentration of potassium ions in peripheral
blood serum have been obtained (Fig. 1). It has been
determined that in blood serum of rats with parental
Walker-256 carcinosarcoma, concentration of К+ was
significantly higher, than in intact (control) animals that
corresponds with data of literature [9]. However, du ring
development of resistance of tumor to doxorubicin,
concentration of potassium ions in serum starts gradu-
ally decreasing, and in tumor, though insignificantly,
but gradually increasing (see Fig. 1). This is probably
connected with the fact that resistant tumor requires
more К+ and more impacts the water-salt metabolism
in organism, than parental (more sensitive to doxorubicin)
Walker-256 carcinosarcoma. Probably, content of water
in organism with resistant tumor is higher, than in organism
with sensitive tumor.
0
5
10
15
20
25
30
35
Intact control Sensitive strain
(65% inhibition
of tumor growth)
Resistant strain
(30% inhibition
of tumor growth)
Resistant strain
(2% inhibition
of tumor growth)
Co
nc
en
tra
tio
n,
m
m
ol
/l
Serum
Tumor
* **
Fig. 1. Potassium levels in blood serum and tumor tissue supernatant
of animals with Walker-256 carcinosarcoma during development
of resistance to doxorubicin (*p < 0.05 compared with sensitive
tumor-bearing rats; **p < 0.05 compared with sensitive tumor)
The same data have been obtained concerning con-
centration of magnesium ions. Concentration of Mg++
in blood serum of animals with sensitive Walker-256 car-
cinosarcoma is also higher, than in intact rats (Fig. 2). This
indicates that malignant process significantly changes
electrolyte balance in orga nism. However, with develop-
ment of tumor resistance to doxorubicin, content of this
cation in blood serum was gradually decreasing, and
in tumor — gradually increasing. As stated above, Mg++
is required for many enzyme reactions associated with
phosphorylation and DNA synthesis. About activation
of intracellular metabolism in the process of development
of malignant tumors drug resistance we pointed out in our
previous studies [14].
Development of resistance of Walker-256 carcino-
sarcoma to doxorubicin is also characterized by changes
in energy metabolism. Firstly, we have studied, how level
Experimental Oncology 37, 19–22, 2015 (March) 21
of glucose is changed in blood serum of animals. It has
been determined that level of this compound in blood
serum of tumor host is significantly lower, than in intact
rats (Fig. 3). Mentioned fact is the consequence of the fact
that malignant tumor is characterized trap of glucose.
As the development of resistance progressed, level
of glucose in blood serum of animals even greater de-
creased. However, this index in tumor, while gradually
lo sing sensitivity to the cytostatic drug, on the contrary,
was increasing (see Fig. 3). This logically corresponds with
dynamics of change of activity of lactate dehydrogenase
both in blood serum and, especially, Walker-256 car-
cinosarcoma (Fig. 4). On the background of reduction
of lactate dehydrogenase activity and, correspondingly,
level of lactate (Fig. 5), the increase of glucose in tumor
was observed. Such changes in mentioned indices indi-
cate gradual decrease of glycolysis activity in tumor cells
during development of resistance to doxorubicin. At that
pyruvate is most likely metabolized in Krebs cycle and
to a lesser degree is used for the formation of lactate. Such
metabolic situation can cause the activation of generation
of Acetyl-CoA that, in turn, stimulates increase of cho-
lesterol that corresponds with the results of our previous
studies [15, 16].
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Intact control Sensitive strain
(65% inhibition
of tumor growth)
Resistant strain
(30% inhibition
of tumor growth)
Resistant strain
(2% inhibition
of tumor growth)
Co
nc
en
tra
tio
n,
m
m
ol
/l
Serum
Tumor
*
**
Fig. 2. Magnesium levels in blood serum and tumor tissue superna-
tant of animals with Walker-256 carcinosarcoma during development
of resistance to doxorubicin (*p < 0.05 compared with sensitive
tumor-bearing rats; **p < 0.05 compared with sensitive tumor)
0
1
2
3
4
5
6
7
8
Intact control Sensitive strain
(65% inhibition
of tumor growth)
Resistant strain
(30% inhibition
of tumor growth)
Resistant strain
(2% inhibition
of tumor growth)
Co
nc
en
tra
tio
n,
m
m
ol
/l
Serum
Tumor
*
**
Fig. 3. Glucose levels in blood serum and tumor tissue supernatant
of animals with Walker-256 carcinosarcoma during development
of resistance to doxorubicin (*p < 0.05 compared with sensitive
tumor-bearing rats; **p < 0.05 compared with sensitive tumor)
Since we studied intensity of glycolysis in tumor cells,
it would be logical to study also functional activity of mi-
tochondria. To solve this question we have used two me-
thodic approaches: polarography (oxygen consumption
by mitochondria) and application of dye JC-1. Data of the
studies are represented in Fig. 6 and 7. As seen in Fig. 6,
development of resistance of Walker-256 carcinosarcoma
to doxorubicin causes the decrease of content of mono-
mer form JC-1 in tumor cells (FL1; green fluorescence).
It indicates higher membrane potential of mitochondria
and increase of functional activity of these organelles.
These results correspond well with data of polarographic
determination of oxygen consumption rate by mito-
chondria. As seen in Fig. 7, development of resistance
to doxorubicin causes increase of oxygen consumption
rate by organelles at phosphorylation of exogenous ADP
in the presence of glutamate. However, it should be men-
tioned that despite changes of bioenergetics indices
in development of drug resistance, intensity of glycolysis
in tumor cells remains high, and intensity of mitochondrial
oxidative phosphorylation — low compared with non-
transformed cells.
0
200
400
600
800
1000
1200
Intact control Sensitive strain
(65% inhibition
of tumor growth)
Resistant strain
(30% inhibition
of tumor growth)
Resistant strain
(2% inhibition
of tumor growth)
Ac
tiv
ity
, U
/l
Serum
Tumor
*
**
Fig. 4. Lactate dehydrogenase activity in blood serum and tumor
tissue supernatant of animals with Walker-256 carcinosarcoma
during development of resistance to doxorubicin (*p < 0.05 com-
pared with sensitive tumor-bearing rats; **p < 0.05 compared with
sensitive tumor)
0
1
2
3
4
5
6
7
Intact control Sensitive strain
(65% inhibition
of tumor growth)
Resistant strain
(30% inhibition
of tumor growth)
Resistant strain
(2% inhibition
of tumor growth)
Co
nc
en
tra
tio
n,
m
m
ol
/l
Serum
Tumor
* **
Fig. 5. Lactate levels in blood serum and tumor tissue supernatant
of animals with Walker-256 carcinosarcoma during development
of resistance to doxorubicin (*p < 0.05 compared with sensitive
tumor-bearing rats; *p < 0.05 compared with sensitive tumor)
Since glucose is known to be able also to degra de
by pentose phosphate pathway [13], we have studied
activity of the first enzyme of this cycle — glucose-
6-phosphate dehydrogenase. It has been determined
that as development of drug resistance in Walker-256 car-
cinosarcoma progresses, gradual increase of activity
of this enzyme occurs (Fig. 8). It is very important that
NADP is co-enzyme for this enzyme. Pentose phosphate
cycle plays double role in the formation of NADPH. In two
stages of pentose phosphate cycle, oxidation of one glu-
22 Experimental Oncology 37, 19–22, 2015 (March)
cose mo lecule occurs and twelve NADPH molecules are
formed. This component does not participate in cellular
oxidation, but is required for the specific reduction reac-
tions, among which are reduction of glutathione, biosyn-
thesis of fatty acids and different steroid hormones [17–
19]. Pentose phosphate pathway is especially important
for those organs and cells, in which these reactions are
actively proceeding — adipocytes, liver, mammary gland,
adrenal gland cortex. Moreover, regulation of water-salt
metabolism is tightly connected with activity of pentose
phosphate cycle. On the other hand, formation of im-
portant metabolites takes place in cycle and especially
ribose-5-phosphate, which is precursor of nucleic acids.
100
100
101
101
102
FL1 LOG
Sensitive strain
(65% inhibition
of tumor growth)
1.72%
4.02% 0.76%
93.5%
FL
2
LO
G
102
103
103
104
104
100
100
101
101
102
FL1 LOG
Resistant strain
(2% inhibition
of tumor growth)
9.10%
3.50% 0.12%
87.28%
FL
2
LO
G
102
103
103
104
104
Fig. 6. The mitochondrial transmembrane electrochemical gra-
dient (Δψm) (JC-1 staining) in Walker-256 carcinosarcoma during
development of resistance to doxorubicin
0
5
10
15
20
25
30
35
40
45
50
Sensitive strain
(65% inhibition
of tumor growth)
Resistant strain
(30% inhibition
of tumor growth)
Resistant strain
(2% inhibition
of tumor growth)
nA
to
m
s
O
2/m
in
·m
g-1
o
f p
ro
te
in *
Fig. 7. Oxygen consumption by tumor cell mitochondria during
exogenous ADP phosphorylation (oxidation substrate — glutamate)
(*p < 0.05 compared with sensitive tumor)
Thus, obtained data show significant changes in con-
tent of K+ and Mg++ and indices of energy metabolism
in blood serum and in tumor cells during resistance de-
velopment of Walker-256 carcinosarcoma to doxorubi-
cin. Results of studies show that as development of drug
resistance in blood serum of tumor host progresses,
decrease of K+, Mg++, glucose and increase of these
indices in tumor tissue are observed. At that gradual
tumor’s loss of sensitivity is characterized by decrease
of glycolysis activity in it and activation of mitochondrial
oxidative phosphorylation and pentose phosphate way
of glucose degradation, which causes more intensive
formation of NADPH. Reduced NADP is required for
many reduction reactions that is very important for pro-
tection of tumor cells from damaging agents.
0
50
100
150
200
250
300
350
400
450
500
Sensitive strain
(65% inhibition
of tumor growth)
Resistant strain
(30% inhibition
of tumor growth)
Resistant strain
(2% inhibition
of tumor growth)
Ac
tiv
ity
, U
/l
*
Fig. 8. Glucose-6-phosphate dehydrogenase activity
in Walker-256 carcinosarcoma supernatant during development of re-
sistance to doxorubicin (*p < 0.05 compared with sensitive tumor)
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