Effectiveness of sodium dichloroacetate against glioma с6 depends on administration schedule and dosage
Background: Anticancer action of sodium dichloroacetate (DCA) could be related to its ability to activate oxidative phosphorylation leading to enhanced generation of reactive oxygen species and induction of apoptosis. On the other hand, activation of oxidative phosphorylation could promote tumor cel...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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| Цитувати: | Effectiveness of sodium dichloroacetate against glioma с6 depends on administration schedule and dosage / A.G. Fedorchuk, O.N. Pyaskovskaya, G.V. Gorbik, I.V. Prokhorova, D.L. Kolesnik, G.I. Solyanik // Experimental Oncology. — 2016 — Т. 38, № 2. — С. 80–83. — Бібліогр.: 23 назв. — англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1860223650197667840 |
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| author | Fedorchuk, A.G. Pyaskovskaya, O.N. Gorbik, G.V. Prokhorova, I.V. Kolesnik, D.L. Solyanik, G.I. |
| author_facet | Fedorchuk, A.G. Pyaskovskaya, O.N. Gorbik, G.V. Prokhorova, I.V. Kolesnik, D.L. Solyanik, G.I. |
| citation_txt | Effectiveness of sodium dichloroacetate against glioma с6 depends on administration schedule and dosage / A.G. Fedorchuk, O.N. Pyaskovskaya, G.V. Gorbik, I.V. Prokhorova, D.L. Kolesnik, G.I. Solyanik // Experimental Oncology. — 2016 — Т. 38, № 2. — С. 80–83. — Бібліогр.: 23 назв. — англ. |
| collection | DSpace DC |
| container_title | Experimental Oncology |
| description | Background: Anticancer action of sodium dichloroacetate (DCA) could be related to its ability to activate oxidative phosphorylation leading to enhanced generation of reactive oxygen species and induction of apoptosis. On the other hand, activation of oxidative phosphorylation could promote tumor cell survival, in particular, via increased ATP synthesis. Such ambiguous effects of DCA could influence its anticancer effectiveness, depending on biological properties of a tumor, schedule of DCA administration and its dosage. The aim of the study was to analyze anticancer effect of DCA against glioma С6 in rats under conditions of different schedules of its administration and various dosages. Materials and Methods: The study was carried out in Wistar rats with intracerebrally transplanted glioma С6 cells. Therapy with DCA was performed as follows: daily for 6 days starting from the second day after tumor cell transplantation (schedule І) or 7th day (schedule ІІ) at a dose of 1.0 g/kg, or daily for 13 days starting from the second day at doses of 1.0; 1.5 or 4.5 g/kg (schedule ІІІ). An influence of hypoxia on anticancer effect of DCA was studied using hypoxic chambers where oxygen content was maintained at a level of 12.5–13% for 3 h after DCA administration to glioma С6 bearing rats. The state of mitochondrial electron transport chain components in tumor cells was studied using electron paramagnetic resonance. Results: It has been shown that therapy with DCA using schedule I resulted in 15% decrease of animals life span (LS; р < 0.05), while the use of schedule II had no effect on this index. Prolonged administration of DCA (schedule ІІІ) resulted in significant antitumor effect and increased LS of rats by 25.5% (p < 0.05). Under hypoxic conditions, treatment with DCA resulted in a significant increase of animal LS by 15–22%. Dosage of DCA had a moderate effect of its anticancer action. Maximal effect, an increase of LS by 34.5% (p < 0.05) was detected at a dose of 1.5 g/kg. It has been shown that anticancer activity of DCA under all studied conditions is not related to its influence on a functional state of tumor cell mitochondria. Conclusion: Anticancer effect of DCA significantly depends on a schedule of its administration; being administered at equal total dose, but dependent on the schedule DCA could cause ambiguous effects varying from tumor growth stimulation to significant anticancer activity. Under hypoxic conditions, anticancer efficacy of DCA against glioma С6 is significantly enhanced.
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80 Experimental Oncology 38, 80–83, 2016 (June)
EFFECTIVENESS OF SODIUM DICHLOROACETATE AGAINST GLIOMA
С6 DEPENDS ON ADMINISTRATION SCHEDULE AND DOSAGE
A.G. Fedorchuk, O.N. Pyaskovskaya, G.V. Gorbik, I.V. Prokhorova, D.L. Kolesnik, G.I. Solyanik*
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv 03022, Ukraine
Background: Anticancer action of sodium dichloroacetate (DCA) could be related to its ability to activate oxidative phosphorylation lead-
ing to enhanced generation of reactive oxygen species and induction of apoptosis. On the other hand, activation of oxidative phosphoryla-
tion could promote tumor cell survival, in particular, via increased ATP synthesis. Such ambiguous effects of DCA could influence its
anticancer effectiveness, depending on biological properties of a tumor, schedule of DCA administration and its dosage. The aim of the
study was to analyze anticancer effect of DCA against glioma С6 in rats under conditions of different schedules of its administration and
various dosages. Materials and Methods: The study was carried out in Wistar rats with intracerebrally transplanted glioma С6 cells.
Therapy with DCA was performed as follows: daily for 6 days starting from the second day after tumor cell transplantation (schedule І)
or 7th day (schedule ІІ) at a dose of 1.0 g/kg, or daily for 13 days starting from the second day at doses of 1.0; 1.5 or 4.5 g/kg (schedule
ІІІ). An influence of hypoxia on anticancer effect of DCA was studied using hypoxic chambers where oxygen content was maintained
at a level of 12.5–13% for 3 h after DCA administration to glioma С6 bearing rats. The state of mitochondrial electron transport chain
components in tumor cells was studied using electron paramagnetic resonance. Results: It has been shown that therapy with DCA using
schedule I resulted in 15% decrease of animals life span (LS; р < 0.05), while the use of schedule II had no effect on this index. Prolonged
administration of DCA (schedule ІІІ) resulted in significant antitumor effect and increased LS of rats by 25.5% (p < 0.05). Under hy-
poxic conditions, treatment with DCA resulted in a significant increase of animal LS by 15–22%. Dosage of DCA had a moderate effect
of its anticancer action. Maximal effect, an increase of LS by 34.5% (p < 0.05) was detected at a dose of 1.5 g/kg. It has been shown
that anticancer activity of DCA under all studied conditions is not related to its influence on a functional state of tumor cell mitochondria.
Conclusion: Anticancer effect of DCA significantly depends on a schedule of its administration; being administered at equal total dose,
but dependent on the schedule DCA could cause ambiguous effects varying from tumor growth stimulation to significant anticancer activ-
ity. Under hypoxic conditions, anticancer efficacy of DCA against glioma С6 is significantly enhanced.
Key Words: sodium dichloroacetate, glioma С6, mitochondrial electron transport chain.
According to statistics of World Health Organization,
an average rate of brain tumors incidence is 10.9–12.8 per
100 000 of population [1]. Nearly 60% of all tumors of cen-
tral nervous system are malignant neoplasmae, among
which gliomas account up to 50–55%. By statistical
data, gliomas yield just 1.4% from all clinically diagnosed
tumors, but the prognosis for glioma patients is the most
unfavorable. An average survival time of the patients
with malignant glioma after its primary diagnosis is ap-
proximately 8 months in Ukraine and 14 months in USA [2].
That’s why the therapy of patients with gliomas of different
grade of malignancy is among the most important prob-
lems of modern clinical oncology.
Despite the development of numerous novel anti-
cancer means, at present time the main approach for
therapy of glioma patients is still a “therapy of despair”,
i.e. surgery, but its effectiveness is insufficiently low [3, 4].
It is supposed that inefficiency of radical removal of glio-
mas is largely caused by tumor invasion into normal sur-
rounding tissues with the formation of indiscrete margins
significantly reduces.
Modern protocols for radiotherapy of malignant glioma
recommend a fractionated irradiation with low daily doses
(> 2 Gy), with a total dose of 60–90 Gy [5]. However, even
the modern methods of irradiation could not help to over-
come an extremely low effectiveness of the therapy, due
to high radioresistance of glioma caused by the develop-
ment of local hypoxia [6].
Chemotherapeutics (including target agents) are
of low effectiveness in the case of gliomas due to their
poor bioavailability [7–10]. For example, in the majority
of cases analysis of biopsy from malignant glioma evi-
dences on the presence of defective but functional hema-
toencephalic barrier which prevents the passage of many
target preparations (especially antibodies against growth
factors and receptors). For treatment of malignant glioma
just one alkylating cytostatic preparation, temozolomide
is used. One should note that a response to therapy with
temozolomide could be observed just in 5–8% patients
in the case of monotherapy, and in approximately in 20%
patients in the case of adjuvant therapy with temozolomide
combined with radiotherapy or surgical treatment [11, 12].
It is known that in a large part of malignant tumors ATP
is generated via glycolysis even in the presence of oxygen
(Warburg’s effect). Aerobic glycolysis is a low-effective
way of ATP generation, but it supports high prolifera-
tive potential of tumor cells and promotes their survival
decreasing the risk of formation of apoptotic stimuli [13,
14]. Therefore, in recent years tumor metabolism, which
provides these growth benefits, is considered as a new
target for anticancer therapy, and compounds capable
to inhibit glycolysis in tumor cells are studied as potentially
effective anticancer agents [15–17]. Among antimetabolic
agents active against many cancer cell types one could
mention sodium dichloroacetate (DCA) [18–20].
Submitted: May 17, 2016.
*Correspondence: E-mail: gsolyanik@gmail.com
Abbreviations used: DCA — sodium dichloroacetate; EPR — elec-
tron paramagnetic resonance; LS — life span; MtETC — mitochon-
drial electron transport chain; PDH — pyruvate dehydrogenase
kinase; ROS — reactive oxygen species.
Exp Oncol 2016
38, 2, 80–83
Experimental Oncology 38, 80–83, 2016 (June)38, 80–83, 2016 (June) (June) 81
DCA inhibits pyruvate dehydrogenase kinase (PDH)
that results in indirect activation of enzymes of PDH com-
plex and consequently in a shift of cell metabolism from
glycolysis toward oxidative phosphorylation. In a case
of activation of oxidative phosphorylation and decreased
intensity of glycolysis upon DCA action, one could expect
an inhibition of tumor cell proliferation caused, in particu-
lar, by significant decrease of the content of metabolites
of pentose-phosphate bypass and pyruvate important for
synthesis of proteins and nucleic acids. DCA-induced ac-
tivation of mitochondrial metabolism may lead to blocking
of tumor cell proliferation and enhancement of reactive
oxy gen species (ROS) generation and apoptosis induc-
tion. However, despite theoretic apparentness of anti-
cancer action of DCA, its effectiveness is not guaranteed.
As it has been shown [21], at a wide concentration range
DCA exerts cytostatic but not cytotoxic action, what is sup-
ported by the data on an absence of its effect toward
intracellular level of ROS, the rate of lactate production
and apoptosis rate in glioma С6 cells.
In addition, it is necessary to note that DCA-induced
activation of oxidative phosphorylation may result not
only in anticancer effect but also may promote tumor cell
survival via increased ATP synthesis. Such ambivalent
influence on tumor cell survival predisposes a variability
of DCA activity [22, 23]. Biologic properties of a tumor,
schedules of DCA administration and its doses could
significantly affect its anticancer effectiveness.
The aim of the study was to analyze anticancer effec-
tiveness of DCA against glioma С6 in rats under conditions
of different schedules of its administration and dosing.
MATERIALS AND METHODS
The study was performed in female Wistar rats
2.5–3 months old weighting 90–150 g, bred at animal
facility of R.E. Kavetsky Institute of Experimental Patho-
logy, Oncology and Radiobiology of the National Academy
of Sciences of Ukraine (IEPOR). The use and care of the
experimental animals have been performed in accordance
with the standard international rules of biologic ethics and
was approved by Institutional Animal Care and Use Com-
mittee. Glioma С6 cell line was obtained from the National
Bank of Cell Lines and Tumor Strains of IEPOR.
Glioma С6 cells were cultured in vitro in DMEM
culture medium supplemented with 10% FBS (Sigma,
USA), 2 mM L-glutamine, and 40 mg/ml gentamycin
at 37 °С in humidified atmosphere with 5% СО2. Trans-
plantation of glioma С6 cells was performed under total
anesthesia via intracerebral inoculation of 0.6•106 cells
in 0.05 ml of physiologic solution in a left parietal area
(anterior horn of left lateral ventricle).
Aqueous DCA solution (Sigma-Aldrich, USA) was
administered daily per os through a tube in a volume
of 3 ml per animal. Therapy with DCA was performed
by different schedules and at different doses as follows:
• schedule І — DCA was administered daily for 6 days
starting from the second day after tumor cell trans-
plantation at a total dose of 1.0 g/kg;
• schedule ІІ — DCA was administered daily for 6 days
starting from the 7th day after tumor cell transplantation
at a total dose of 1.0 g/kg;
• schedule ІІІ — DCA was administered daily for 13 days
starting from the second day at total doses of 1.0;
1.5 or 4.5 g/kg.
All animals from corresponding control groups received
3.0 ml of water for injections by the schedules for DCA
administration. There were 13–15 rats per each group.
At day 14 after tumor cell inoculation 4–5 rats from each
group were sacrificed under ether narcosis, blood was
collected; brain tissue was taken for further examination.
The changes in survival time (CST) of remaining ani-
mals served as an index of anticancer effect of the treat-
ment calculated by a formula:
CST (%) = 100 • (ST – STC)/STC,
where ST and STС are survival time of rats from experimen-
tal and control groups, respectively.
An influence of hypoxia (inhibitor of oxidative phos-
phorylation) on anticancer effect of DCA was studied using
hypoxic chambers where oxygen content was maintained
at a level of 12.5–13% for 3 h after DCA administration
to glioma С6 bearing rats. Content of oxygen in hypoxic
chambers was controlled using oxymeter ISO2 (World
Precision Instruments, USA). Anticancer effects of the
treatment were evaluated by prolongation of survival time
of animals with glioma С6.
The changes of the state of mitochondrial electron
transport chain (MtETC) components in tumor cells were
analyzed using the method of electron paramagnetic reso-
nance. Electron paramagnetic resonance (EPR)-analysis
of the samples was performed at 77 К using spectro-
photometer Е-109 Varian (USA). By the data of EPR
spectroscopy, the levels of reduced non-heme iron-sulfur
(Fe-S) centers (g = 1.94) of MtETC proteins, nitrosyl (NO)
complexes of heme iron (gсер = 2.01) and Fe-S nitrosyl
complexes (gсер = 2.03) were determined.
Statistical analysis of the data was performed by de-
scriptive methods, correlation analysis, non-linear re-
gression analysis, Student’s t-test, and Mann — Whitney
U test, with the use of Microsoft Excel, Microcal Origin and
Statistica. The data are presented as M ± m.
RESULTS AND DISCUSSION
The results of the study have shown that an effective-
ness of DCA against glioma С6 depends on admini stration
schedule and is significantly increased if the animals are
kept under hypoxic conditions for 3 h after administration
of this agent.
As one may see (Table 1), therapy with DCA by sche-
dule I resulted in 15% decrease of animals life span (LS;
р < 0.05). Upon application of schedule II which differs
from schedule I by later terms of treatment initiation,
no effect on LS of experimental animals was observed.
Prolonged administration of DCA (schedule ІІІ) resulted
in significant antitumor effect and increased LS of rats
by 25.5% (p < 0.05).
Usually in preclinical trials an effectiveness of antican-
cer agents administration of which begins at the back-
ground of an already developed tumor (days 7–10 after
82 Experimental Oncology 38, 80–83, 2016 (June)
tumor cell inoculation), is lower compared with that if such
agents are administered at earlier terms (day 2 after tumor
cell inoculation). However, our data have demonstrated
an opposite picture: an efficacy of DCA is higher against
a developed tumor. It is known that a developed tumor
is characterized by the development of intratumoral hy-
poxia. An increase of LS of rats with glioma С6 after pro-
longed administration of DCA at the background of a de-
veloped tumor could be related with the deve lopment
of intratumoral hypoxia as far as DCA-induced activation
of oxidative phosphorylation under conditions of oxygen
deficiency significantly decreases ATP synthesis and, con-
sequently, may result in tumor cell death. This assumption
is in agreement with the results of the study that analyzed
an influence of hypoxia on an effectiveness of cytotoxic/
cytostatic action of DCA against glioma С6 cells in vitro.
As it has been shown [21], significant enhancement
of cytotoxic action of DCA against glioma С6 cells under
hypoxic conditions (triple decrease of DCA IC50 vs that
under normoxic conditions of culturing) was determined
by high-level DCA-induced necrosis of the cells.
Administration of DCA under hypoxic conditions
resulted in significant increase of its anticancer effect.
In particular, in the case of schedule I DCA administra-
tion under hypoxic conditions had no effect on LS of ex-
perimental animals while in an absence of hypoxia such
therapy stimulated tumor process and caused 15%
reduction of LS. Being administered by sche dule II under
hypoxic conditions, DCA significantly prolonged LS of rats
by 22% compared to the animals treated with DCA under
conditions of normoxia (Table 1). However, it is neces-
sary to note that significant variability of antiglioma action
of DCA upon different schedules of its administration was
observed under conditions of hypoxia as well as normoxia.
Table 1. Anticancer effectiveness of DCA administered by different schedules
under conditions of normoxia and hypoxia
Type of therapy
Schedule of DCA administration Change
of LS, %Number Beginning
(day)
Duration of treat-
ment (days)
DCA І 2nd 6 −15.0
ІІ 7th 6 0.0
ІІІ 2nd 13 +25.5
DCA + hypoxia І 2nd 6 0.0
ІІ 7th 6 +22.0
Among possible mechanisms of anticancer action
of inhibitors of energetic metabolism of tumor cells, in-
cluding DCA, one could mention an ability of these agents
to exert a damaging effect on a functional state of MtETC
in tumor cells through activation of oxidative phosphoryla-
tion, hypoxia and possible defectiveness of mitochondrial
system. That’s why we have studied an influence of DCA
on a functional state of MtETC using EPR spectroscopy.
High invasiveness of glioma complicates an accurate
separation of tumor and normal tissues. That’s why for
preparation of EPR samples we have used the tissue
of cerebral hemisphere with the tumor, and for a compari-
son — the tissue of cerebral hemisphere without tumor.
As indexes of functional state of MtETC we have used
the levels of NO complexes of mitochondrial heme iron
(that reflects a damaging action of ROS and nitrogen
toward ETC), and the content of Fe-S centers, directly
reflecting a functional state of this energetic system.
An analysis of DCA effects under conditions of nor-
moxia and hypoxia on a functional state of MtETC in glioma
С6 cells revealed an absence of correlation between
MtETC functionality and LS of experimental animals
(Table 2).
As shown in Table 2, administration of DCA by all
schedules under conditions of normoxia and hypoxia
had no effect on the levels of Fe-S centers in cerebral
hemisphere with glioma С6 even at the background
of significant (more than 46.7%) increase of nitrosylation
level of heme proteins registered after DCA adminis-
tration under normoxic conditions. It is supposed that
a decrease of the content of Fe-S centers in tumor tissue
characterizes a malfunction of MtETC resulting in tumor
cell death. Unchanged content of Fe-S centers indicated
that anticancer action of DCA is not related to its influence
on a functional state of mitochondria in glioma С6 cells.
Table 2. Influence of DCA administered by different schedules under conditions
of normoxia and hypoxia on the indexes of a functional state of MtETC in the cells
of cerebral hemisphere with glioma
Group of animals Cerebral hemisphere with glioma
Schedule І Schedule ІІ Schedule ІІІ
Intensity of EPR signal for NO-heme complexes (g = 2.01; a.u.)
Control 100.0 ± 2.9 100.0 ± 6.5 100.0 ± 1.4
DCA 153.1 ± 21.7* 146.7 ± 13.0* 152.4 ± 20.8*
DCA + hypoxia 87.4 ± 14.3 148.4 ± 9.8* 103.6 ± 10.7
Intensity of EPR signal for Fe-S centers (g=1.94; a.u.)
Control 100.0 ± 40.4 100.0 ± 19.1 100.0 ± 28.9
DCA 97.5 ± 17.4 112.4 ± 23.0 83.3 ± 19.2
DCA + hypoxia 100.6 ± 37.3 115.1 ± 40.0 108.3 ± 16.0
Note: *p < 0.05, differences are significant as compared to the value for control.
Contrary to the brain tissue samples with glioma, the
content of NO-heme complexes in normal brain tissue
after DCA administration by schedules І and ІІІ significantly
decreased by more than 17% under conditions of normo-
xia and hypoxia (Table 3). However, the level of Fe-S cen-
ters in normal brain tissue remained unaltered.
Table 3. Influence of DCA administered by different schedules under conditions
of normoxia and hypoxia on the indexes of functional state of MtETC in the cells
cerebral hemisphere without glioma
Group of animals Cerebral hemisphere without glioma
Schedule І Schedule ІІ Schedule ІІІ
Intensity of EPR signal for NO-heme complexes (g = 2.01; a.u.)
Control 100.0 ± 3.4 100.0 ± 4.3 100.0 ± 2.7
DCA 82.8 ± 3.4* 119.6 ± 2.9* 82.9 ± 3.6*
DCA + hypoxia 72.1 ± 9.9* 123.0 ± 9.1 56.8 ± 20.4*
Intensity of EPR signal for Fe-S centers (g = 1.94; a.u.)
Control 100.0 ± 34.0 100.0 ± 5.3 100.0 ± 20.0
DCA 129.0 ± 37.7 103.2 ± 23.8 101.3 ± 28.1
DCA + hypoxia 109.9 ± 17.3 105.3 ± 21.2 104.0 ± 19.0
Note: *p < 0.05, differences are significant as compared to the value for control.
The study of effects of DCA dosing on LS of rats was
done by the schedule with the highest anticancer ef-
ficacy. It has been shown that DCA dose moderately af-
fected an efficacy of its antiglioma action (Figure, Table 4).
The maximal effect was registered if DCA was adminis-
tered at a dose of 1.5 g/kg: LS of experimental animals
increased by 34.5% (p < 0.05). An elevation of DCA dose
up to 4.5 g/kg did not lead to the further rise of its efficacy:
the LS of rats was significantly higher than that in control
animals not treated with DCA, but didn’t differ from that
in animals treated with a dose of 1.0 g/kg.
An analysis of DCA effects upon its prolonged ad-
ministration at different doses did not reveal significant
changes in the nitrosylation levels of heme proteins and
Experimental Oncology 38, 80–83, 2016 (June)38, 80–83, 2016 (June) (June) 83
content of Fe-S centers in the cells of cerebral hemi-
sphere with glioma (Table 5), and normal brain tissue
(Table 6).
0
20
40
60
80
100
0 5 10 15 20 25 30
Nu
m
be
r o
f a
liv
e
ra
ts
, %
Life time, days
0.0 g/kg
1.0 g/kg
1.5 g/kg
4.5 g/kg
Figure. Survival curves of rats with glioma С6 treated with DCA
administered at different doses by schedule III
Table 4. Dependence between DCA dosing and its antiglioma effectiveness
Total dose,
g/kg
Schedule of ad-
ministration
Beginning
(day)
Duration of ther-
apy (days)
Change of LS,
%
1.0 III 2nd 13 +25.5
1.5 III 2nd 13 +34.5
Table 5. Effects of DCA administered at different doses on the indexes
of a functional state of MtETC in the cells of cerebral hemisphere with glioma
Group of animals Cerebral hemisphere with glioma
DІ D2 D3
Intensity of EPR signal for NO-heme complexes (g = 2.01; a.u.)
Control 100.0 ± 1.4 100.0 ± 3.5 100.0 ± 3.5
DCA 152.4 ± 20.8* 93.1 ± 13.0 103.0 ± 3.1
Intensity of EPR signal for Fe-S centers (g=1.94; a.u.)
Control 100.0 ± 28.9 100.0 ± 5.5 100.0 ± 5.5
DCA 83.3 ± 19.2 88.1 ± 12.1 101.2 ± 10.6
Note: *p < 0.05, differences are significant as compared to the value for control.
Table 6. Effects of DCA administered at different doses on the indexes
of a functional state of MtETC in the cells of cerebral hemisphere without glioma
Group of animals Cerebral hemisphere without glioma
DІ D2 D3
Intensity of EPR signal for NO-heme complexes (g = 2.01; a.u.)
Control 100.0 ± 2.7 100.0 ± 13.0 100.0 ± 13.0
DCA 82.9 ± 3.6* 94.2 ± 2.7 79.4 ± 5.4
Intensity of EPR signal for Fe-S centers (g = 1.94; a.u.)
Control 100.0 ± 20.0 100.0 ± 15.5 100.0 ± 15.5
DCA 101.3 ± 28.1 118.6 ± 3.6 102.4 ± 6.9
Note: *p < 0.05, differences are significant as compared to the value for control.
An absence of such changes along with a high anti-
cancer efficacy of DCA (especially at a dose of 1.5 g/kg)
once more demonstrated that effects of DCA against
glioma С6 have no relation to a functional state of tumor
cell mitochondria.
In conclusion, the results of our study have shown that
anticancer effectiveness of DCA significantly depends
on the schedule of its administration whereupon it varies
from a significant decrease of LS directly correlating with
stimulation of tumor growth, to significant anticancer ef-
fect and increased LS of rats by 25.5%. Prolonged met-
ronomic administration of DCA provides better anticancer
effectiveness with low variability between the doses. Also,
it has been demonstrated that hypoxic conditions of ani-
mal keeping significantly elevate an antiglioma efficacy
of DCA. Along with this, anticancer activity of this agent
is not related to its effects on a functional state of tumor
cell mitochondria.
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Copyright © Experimental Oncology, 2016
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| id | nasplib_isofts_kiev_ua-123456789-137992 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 1812-9269 |
| language | English |
| last_indexed | 2025-12-07T18:19:08Z |
| publishDate | 2016 |
| publisher | Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| record_format | dspace |
| spelling | Fedorchuk, A.G. Pyaskovskaya, O.N. Gorbik, G.V. Prokhorova, I.V. Kolesnik, D.L. Solyanik, G.I. 2018-06-17T20:29:49Z 2018-06-17T20:29:49Z 2016 Effectiveness of sodium dichloroacetate against glioma с6 depends on administration schedule and dosage / A.G. Fedorchuk, O.N. Pyaskovskaya, G.V. Gorbik, I.V. Prokhorova, D.L. Kolesnik, G.I. Solyanik // Experimental Oncology. — 2016 — Т. 38, № 2. — С. 80–83. — Бібліогр.: 23 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/137992 Background: Anticancer action of sodium dichloroacetate (DCA) could be related to its ability to activate oxidative phosphorylation leading to enhanced generation of reactive oxygen species and induction of apoptosis. On the other hand, activation of oxidative phosphorylation could promote tumor cell survival, in particular, via increased ATP synthesis. Such ambiguous effects of DCA could influence its anticancer effectiveness, depending on biological properties of a tumor, schedule of DCA administration and its dosage. The aim of the study was to analyze anticancer effect of DCA against glioma С6 in rats under conditions of different schedules of its administration and various dosages. Materials and Methods: The study was carried out in Wistar rats with intracerebrally transplanted glioma С6 cells. Therapy with DCA was performed as follows: daily for 6 days starting from the second day after tumor cell transplantation (schedule І) or 7th day (schedule ІІ) at a dose of 1.0 g/kg, or daily for 13 days starting from the second day at doses of 1.0; 1.5 or 4.5 g/kg (schedule ІІІ). An influence of hypoxia on anticancer effect of DCA was studied using hypoxic chambers where oxygen content was maintained at a level of 12.5–13% for 3 h after DCA administration to glioma С6 bearing rats. The state of mitochondrial electron transport chain components in tumor cells was studied using electron paramagnetic resonance. Results: It has been shown that therapy with DCA using schedule I resulted in 15% decrease of animals life span (LS; р < 0.05), while the use of schedule II had no effect on this index. Prolonged administration of DCA (schedule ІІІ) resulted in significant antitumor effect and increased LS of rats by 25.5% (p < 0.05). Under hypoxic conditions, treatment with DCA resulted in a significant increase of animal LS by 15–22%. Dosage of DCA had a moderate effect of its anticancer action. Maximal effect, an increase of LS by 34.5% (p < 0.05) was detected at a dose of 1.5 g/kg. It has been shown that anticancer activity of DCA under all studied conditions is not related to its influence on a functional state of tumor cell mitochondria. Conclusion: Anticancer effect of DCA significantly depends on a schedule of its administration; being administered at equal total dose, but dependent on the schedule DCA could cause ambiguous effects varying from tumor growth stimulation to significant anticancer activity. Under hypoxic conditions, anticancer efficacy of DCA against glioma С6 is significantly enhanced. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Original contributions Effectiveness of sodium dichloroacetate against glioma с6 depends on administration schedule and dosage Article published earlier |
| spellingShingle | Effectiveness of sodium dichloroacetate against glioma с6 depends on administration schedule and dosage Fedorchuk, A.G. Pyaskovskaya, O.N. Gorbik, G.V. Prokhorova, I.V. Kolesnik, D.L. Solyanik, G.I. Original contributions |
| title | Effectiveness of sodium dichloroacetate against glioma с6 depends on administration schedule and dosage |
| title_full | Effectiveness of sodium dichloroacetate against glioma с6 depends on administration schedule and dosage |
| title_fullStr | Effectiveness of sodium dichloroacetate against glioma с6 depends on administration schedule and dosage |
| title_full_unstemmed | Effectiveness of sodium dichloroacetate against glioma с6 depends on administration schedule and dosage |
| title_short | Effectiveness of sodium dichloroacetate against glioma с6 depends on administration schedule and dosage |
| title_sort | effectiveness of sodium dichloroacetate against glioma с6 depends on administration schedule and dosage |
| topic | Original contributions |
| topic_facet | Original contributions |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/137992 |
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