Ultrastructural changes in tumor cells treated with liposomal forms of anticancer drugs
Aim: To determine the main ultrastructural changes in MCF-7 sublines sensitive and resistant to cytotoxic action of anticancer drugs, resulting from the treatment with conventional and liposomal forms of cisplatin and doxorubicin. Methods: Electron microscopy, light microscopy, MTT-test. Results: It...
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| Опубліковано в: : | Experimental Oncology |
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| Дата: | 2010 |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2010
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| Цитувати: | Ultrastructural changes in tumor cells treated with liposomal forms of anticancer drugs / O.V. Yurchenko, N.V. Rusetskaya, L.A. Naleskina, V.F. Chekhun // Experimental Oncology. — 2010. — Т. 32, № 1. — С. 24-28. — Бібліогр.: 27 назв. — англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1859674015342264320 |
|---|---|
| author | Yurchenko, O.V. Rusetskaya, N.V. Naleskina, L.A. Chekhun, V.F. |
| author_facet | Yurchenko, O.V. Rusetskaya, N.V. Naleskina, L.A. Chekhun, V.F. |
| citation_txt | Ultrastructural changes in tumor cells treated with liposomal forms of anticancer drugs / O.V. Yurchenko, N.V. Rusetskaya, L.A. Naleskina, V.F. Chekhun // Experimental Oncology. — 2010. — Т. 32, № 1. — С. 24-28. — Бібліогр.: 27 назв. — англ. |
| collection | DSpace DC |
| container_title | Experimental Oncology |
| description | Aim: To determine the main ultrastructural changes in MCF-7 sublines sensitive and resistant to cytotoxic action of anticancer drugs, resulting from the treatment with conventional and liposomal forms of cisplatin and doxorubicin. Methods: Electron microscopy, light microscopy, MTT-test. Results: It has been shown that the phenomenon of drug resistance is associated with complication of ultrastructural organization of cells and more high differentiation by the main cytomorphologic characteristics which promote their resistance to cytotoxic action of anticancer preparations. Cytoarchitectonics of all resistant cells possesses common patterns and doesn’t depend on the particular drugs toward which the resistance has been developed. It has been shown that the cells of the parental form MCF-7 line are more sensitive to cytotoxic action of doxorubicin than to cisplatin. Liposomal forms of anticancer drugs used at the same concentrations that the conventional ones, especially that of doxorubicin, caused more expressed alterations in ultrastructural organization of cells of all studied sublines with dominance of apoptotic processes. Conclusion: Evaluating an effect of equal concentrations of cisplatin and doxorubicin in conventional and liposomal forms, one may conclude on higher cytotoxic action of doxorubicin vs. cisplatin that is expressed in a wider spectrum of ultrastructural changes of cell architectonics in different sublines of MCF-7 cells and higher rate of apoptosis.
|
| first_indexed | 2025-11-30T14:46:13Z |
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Experimental Oncology 32, 23–28, 2010 (March) 23
Cancer chemotherapy occupies the leading posi-
tion in treatment of cancer patients, but an absence
of selectivity of action of the majority of anticancer
drugs and often an expressed resistance of tumor
cells to performed chemotherapy remains a major
challenge for clinical oncology limiting successful
therapy of cancer patients.
There are numerous approaches for elevation of the
efficacy of medicinal preparation action, in particular, the
development of new technologies for creation of sys-
tems for directed transport of cancer drugs. Liposomes,
especially spatially stabilized ones, are considered
optimal variants of carriers used for targeted delivery of
medicinal preparations to tumor cells. Such liposomes
acquire the property to enter easily solid tumors through
the walls of newly developed during neoangiogenesis
vasculature and, being accumulated there, to act as
a system constantly releasing medicinal preparations
[1–3], what is considered in the literature [4] as an effect
of elevated vessel permeability (EPR-effect). In a num-
ber of experimental studies it has been demonstrated
higher accumulation of liposomal anticancer drugs in
cells compared to their free forms [5]. The use of liposo-
mal forms of anticancer drugs in modern chemotherapy
created an alternative approach that from one side, al-
lows decrease significantly total toxic influence due to
their selective accumulation in tumor tissue, and from
other side, — to elevate antitumor effect. Protrac tedly
circulating liposomes and other macromolecular carriers
may increase drug depositing in tumors [6].
If anticancer drugs are included into liposomes,
their distribution in body significantly decreases; while
their concentration in tumor increases, thus unspecific
toxicity is lower [7].
There are the data showing that liposomal systems
of drug delivery may overcome an activity of trans-
port proteins of multiple drug resistance (MDR) even
in highly resistant tumors. By endocytosis, liposomes
deliver the preparation in cytoplasm and its direct in-
teraction with P-glycoprotein (P-gp) located in plasma
membrane is decreased. According to observations
of Michieli et al. [8], incubation of cells with MDR
patterns and P-gp hyperexpression with liposomal
daunorubicin inserted into membrane composed from
phosphotidylcholine/cholesterol, led to its significant
intracellular accumulation compared with its free
form and to 4–5-fold increase of cytotoxic effect. The
mechanism of such action is not studied completely
yet. However, experimental data evidence that MDR of
cells modulated by P-gp, may be altered significantly
by optimally designed liposome composition and
inserted cancer drugs [9, 10]. The results of in vitro
studies and clinical studies with the use of liposomal
doxorubicin have shown that drug resistance may
be partially reversed if one would use liposomal form
of doxorubicin or other cancer grugs [11–13].
Cisplatin and doxorubicin are widely used for
thera py of cancer patients, but differ in their mecha-
nism of action. It has been demonstrated that the
use of liposomal forms of the drugs is beneficial to
their conventional analogs. Despite multiplicity of
fundamental studies directed on the research of pe-
culiarities of interaction between liposomal forms of
anticancer drugs with cells, presently many questions
remain unanswered. There is no data on the character
of alterations of cells sensitive to cytotoxic action of
anticancer drugs, after their treatment with liposomal
analogs versus that of the cells resistant to antican-
ULTRASTRUCTURAL CHANGES IN TUMOR CELLS TREATED WITH
LIPOSOMAL FORMS OF ANTICANCER DRUGS
O.V. Yurchenko*, N.V. Rusetskya, L.A. Naleskina, V.F. Chekhun
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine,
Kiev 03022, Ukraine
Aim: To determine the main ultrastructural changes in MCF-7 sublines sensitive and resistant to cytotoxic action of anticancer drugs,
resulting from the treatment with conventional and liposomal forms of cisplatin and doxorubicin. Methods: Electron microscopy, light
microscopy, MTT-test. Results: It has been shown that the phenomenon of drug resistance is associated with complication of ultrastruc-
tural organization of cells and more high differentiation by the main cytomorphologic characteristics which promote their resistance to
cytotoxic action of anticancer preparations. Cytoarchitectonics of all resistant cells possesses common patterns and doesn’t depend on
the particular drugs toward which the resistance has been developed. It has been shown that the cells of the parental form MCF-7 line
are more sensitive to cytotoxic action of doxorubicin than to cisplatin. Liposomal forms of anticancer drugs used at the same concentra-
tions that the conventional ones, especially that of doxorubicin, caused more expressed alterations in ultrastructural organization of cells
of all studied sublines with dominance of apoptotic processes. Conclusion: Evaluating an effect of equal concentrations of cisplatin and
doxorubicin in conventional and liposomal forms, one may conclude on higher cytotoxic action of doxorubicin vs. cisplatin that is expressed
in a wider spectrum of ultrastructural changes of cell architectonics in different sublines of MCF-7 cells and higher rate of apoptosis.
Key Words: ultrastructure, tumor cell resistance, liposome, doxorubicin, cisplatin.
Received: January 25, 2010.
*Correspondence: Fax: +38 (044) 258-16-56
Abbreviatons used: DDP — conventional forms of cisplatin; DDP-
Lip — liposomal forms of cisplatin; Dox — conventional forms
of doxorubicin; Dox-Lip — liposomal forms of doxorubicin; GER —
granular endoplasmic reticulum; MDR — multiple drug resistance;
Р-gр — Р-glycoprotein.
Exp Onco 2010
32, 1, 23–28
Experimental Oncology 32, 23–28, 2010 (March) 25
ment of drug resistance, the cells became somewhat
larger, and on their surface one could see an appear-
ance of expressed protrusions of plasma membrane
and increased number of microvilli of different length.
MCF-7/Dox cells possess more spread shape what
may be observed during their examination by light
microscopy. With the use of electron microscopy it
has been detected that cell nuclei are characterized
by appearance of notable regions of heterochromatin
located close to inner side of nuclear membrane, and
by altered shape. The majority of cells possess rug-
ged shape of nucleus due to appearance of nuclear
membrane invaginations that respectively increase
its area (Fig. 1, b). Such patterns were not observed
in drug-sensitive cells. In nucleus one or sometimes
two nucleoli located on periphery are detected. Cells
of MCF-7/DDP and MCF-7/Dox sublines are cha-
racterized by higher density what is related to a large
number of free ribosomes that tend to aggregate with
the formation of polysomes. High electronic density
is also related to big quantity of glycogen that forms
characteristic rosettes all around cytoplasm. One may
detect the increase of the number of all cell organelles.
Mitochondria possessing the structure analogous to
that of original MCF-7 cells, are located throughout
cell perimeter, sometimes forming small aggregations
close to nuclear invaginations. During development of
drug resistance GER also underwent alterations and
occupies large area in cells and is presented by long
channels with significant number of ribosomes on its
outer membranes. One should point on a partial vacuo-
lization of channels tubules in some cells that may be
related to increased protein synthesis [18].
a
b
Fig. 1. Ultrastructure of MCF-7 cells: (a) parental cells, which
are sensitive to cytotoxic action of antitumor drugs, x 6900; (b)
variant with acquired resistance to doxorubicin, x 8400
Golgi complex in the majority of cells is composed
from 2–3 loci placed in one region of cytoplasm, not
far from nucleus. Each locus has a large number of
microvesicles that from one side, are bound to few
flat cisterns, and from other side — with large enough
vacuoles. The presence of well developed numerous
structural components of the complex in resistant
cells vs sensitive MCF-7 cells evidences on functional
loading of this cell organelle [19]. Using immunocyto-
chemical analysis of resistant cells, Molinari et al. [21]
have been shown that P-gp was present not only on the
surface of plasma membrane, but was also located in
cytoplasm, in particular on vesicles of Golgi complex
and lyzosomal system components [20], but not on
mitochondrial membranes.
In cytoplasm of MCF-7/DDP and MCF-7/Dox cells,
one may detect also a big number of lyzosome-like
formations, electron-transparent vesicles of different
size, and lipid inclusions in some cells. It’s necessary
to note the presence of some cell polymorphism that
was observed in parental MCF-7 cell line as well.
So, ultrastructure of resistant cells evidences on
elevation of synthetic processes in the cells (increased
number of free ribosomes and their aggregation in
polysomes, higher numbers of GER components and
elements of Golgi complex). The data point on altera-
tion of cell metabolism that causes modification of their
architecture [22, 23].
Ultrastructural changes in MCF-7 cells caused
by action of conventional and liposomal forms of
cisplatin and doxorubicin. Alterations of parental vari-
ant of MCF-7 cells caused by treatment with conventional
forms of cisplatin (DDP) and doxorubicin (Dox) were
of similar character but differ by the degree of expression
of toxic manifestations. Оur study has shown that paren-
tal MCF-7 cells are more sensitive to Dox that causes
more expressed cytotoxic alterations than DDP does.
In the majority of cells dystrophic changes were
detected that were expressed in significant vacuoli-
zation of cell cytoplasm and decrease of the number
of cytoplasmic organelles. Some cells were in a state
of necrobiosis, with significant nuclear alterations, in
particular, with loosen euchromatin, while cytoplasm
contained a big number of vacuoles of various sizes
(Fig. 2, а). There were found the cells in necrotic state
where integrity of cell membrane was disturbed, and
cytoplasm components were disorganized. The num-
ber of cells with significant toxic manifestations was
higher in the case of Dox treatment than that of DDP
treatment. In the majority of studied cells nuclei with
low electronic density and cytoplasm with large num-
ber of vacuoles and dense single mitochondria were
observed, while clear detection of other organelles
was problematic (Fig. 2, b).
Apoptotic cell death upon the action of conventional
forms of the preparations was more characteristic for
cells treated with doxorubicin, where all stages of apop-
tosis (from initial cytoplasm and nuclei condensation
to formation of apoptotic bodies) have been observed.
DDP Action also led to apoptosis of small part of sensitive
26 Experimental Oncology 32, 23–28, 2010 (March)
cells, but here the quantitative domination of irrevers-
ibly altered cells and cells in necrobisis state have been
detected. Potential mechanism of cell death upon DDP
influence is thought to be apoptosis that develops due
to interaction of DDP with cell DNA; however, in some
cases at early stages of apoptosis initiation, damage
of cytoplasmic proteins occurs as well leading to necrotic
damage of cells [24]. Despite the fact that apoptosis and
necrosis are the forms of cell death differing by morpho-
logical and biochemical patterns, both their types may
be present simultaneously in tissues and cultured cells
upon the action of DDP [25]. The degree of intracellular
damage caused by DDP may affect the form of cell death
as a result of necrosis or not fulfilled apoptotic program,
i. e. cell death induced by DDP not always responds to
“classic” apoptosis, where an important role is played
by preparation dose and cell cycle phase at the moment
of DDP treatment [26].
Action of Dox in the majority of cases leads to
development of apoptosis which efficacy depends
on the dose of the preparation and incubation period.
Action of liposomal drugs on parental MCF-7 cells
also led to death of a part of the cells. A number of cells
that died upon the action of liposomal forms of the pre-
parations, has increased at average by 3–5%, and also in
the majority of cells significant cytotoxic alterations that
manifest themselves in dystrophy of different degree,
have appeared. It’s necessary to note that cells became
bigger, possibly, because of expressed vacuolarization
of cytoplasm (Fig. 2, c). Dystrophic cell changes are also
expressed in damaged structure of mitochondria which
number decreased. Cristae deformation and their lower
numbers are related to lower activity of mitochondria.
Apart from this, vacuolization of the part of mitochondria
was detected, pointing on cell autolysis. GER is presented
by widened cisterns, on which surface there is a moder-
ate number of ribosomes. A part of cells died due to
necrosis. Upon the action of DDP-Lip there was observed
a characteristic dominance of expressed dystrophic
processes that finally lead to cell death, while apoptotic
cells are rarely observed. For Dox-Lip there was detected
a characteristic dominance of cells with morphologic
signs of apoptosis (Fig. 2, d).
Thus, upon the action of liposomal forms of the
anticancer drugs which concentration is equal to that
of conventional forms, on drug-sensitive MCF-7 cells,
one may detect more expressed cytotoxic damage of
cell components, elevated apoptosis rate, especially in
the case of Dox-Lip, compared to conventional forms.
Such effect may be related to higher accumulation
of liposomal drugs compared to conventional forms
as well as their different intracellular distribution [6].
Ultrastructural changes of resistant MCF-7
cells caused by action of conventional and liposo-
mal forms of cisplatin and doxorubicin. Alteration
of ultrastructure of MCF-7/DDP cells upon the action
of DDP manifested themselves by the presence of dys-
trophy signs: one could detect a large number of cells
with electron-transparent vacuoles (Fig. 3, а). In a part
of cells significant changes related to disorganization of
all cell components and cytoplasmic matrix evidencing
on cytotoxic damage, have been detected. Cell sur-
face was bigger via formation of multiple cytoplasmic
bubbles bound to membrane. The number of apoptotic
cells was insignificant similarly to that of sensitive MCF-7
cells. Homotypic changes of resistant and sensitive cells
treated with conventional form of the preparation may be
explained by its concentration (IC10 for all studied cells).
a
b
с
d
Fig. 2. Changes in ultrastructure of MCF-7 cells, which are
sensitive to the cytotoxic action of antitumor drugs: (a) influ-
ence of DDP, x 5000; (b) influence of Dox, x 3300; (c) influence
of DDP-Lip, x 5000; (d) influence of Dox-Lip, x 3300
Experimental Oncology 32, 23–28, 2010 (March) 27
a
b
с
d
Fig. 3. Changes in ultrastructure of MCF-7/DDP and MCF-7/Dох
cells upon the influence of antitumor drugs: (a) influence of free
DDP on MCF-7/DDP cells, x 5000; (b) influence of DDP-Lip on
MCF-7/DDP cells, x 5000; (c) influence of Dox on MCF-7/Dох
cells, x 15 000; (d) influence of Dox-Lip on MCF-7/Dох cells, x 3000
Upon the influence of DDP-Lip toxic patterns are re-
lated not only to cytoplasm, but to nuclear ultrastructure
where loosen euchromatin could be detected. In nucle-
oli, granular and dense fibrillar components presented
by RNA-containing ribosome subunits, were domina-
ting. In cytoplasm of the majority of cells disorganization
of cell organelles occurred, electron-transparent area
in cytoplasm appeared, vacuolization of cytoplasm and
mitochondria were detected (Fig. 3, b). So, treatment of
resistant cells with DDP-Lip led to more expressive toxic
effect than that with conventional form of the drugs at
equal concentration (IC10) did.
Changes of doxorubicin-resistant cells upon the
influence of Dox evidence on the presence of dystro-
phy of various degrees — cytoplasm disorganization,
altered density of cytoplasmic matrix, vacuolization
of cytoplasm, mitochondria, and Goldgi complex
(Fig. 3, c). Electron-microscopic changes of nuclei
were characterized by altered chromatin structure that
was dispersed in nucleus as small granules without
formation of characteristic aggregation along nuclear
membrane. Experimental studies performed in vitro
by other authors with the use of confocal microscopy,
have shown that in resistant ovarian cancer cells of
SKVLB line and MCF-7/ADR cells, doxorubicin is loca-
lized and transported mainly by cytoplasmic vesicles.
The fact that in sensitive cells the preparation may have
in part nuclear localization, what possibly determines
its higher cell toxicity, is very important. Intraliposomal
preservation of doxorubicin alters its distribution in
resistant cells with partial transfer to nuclear compart-
ments. So, liposomal doxorubicin may enter the cells
with MDR phenotype bypassing vesicular transport
and increasing its anticancer activity [27].
An influence of Dox-Lip on doxorubicin-resistant
cells led to elevation of its toxic effect resulting in
acceleration of dystrophic processes in cells, and
increased number of cells in necrobiosis state with
the tendency to necrotic death. It’s necessary to note
that among the majority of dying cells, all stages of
apoptosis have been detected (Fig. 3, d).
The performed electron-microscopic study has
shown that common cytomorphological manifesta-
tions evidencing on toxic effect of studied cancer
drugs, account dystrophic alterations in cytoplasm,
nucleus, and cell organelles, and also death of the
part of cells by necrosis and apoptosis, what is more
notable in the case of treatment with liposomal phar-
maceutical forms, especially Dox-Lip.
In total, evaluating an effect of action of equal con-
centrations of cisplatin and doxorubicin in conventional
and liposomal forms, one may conclude on higher
cytotoxic action of doxorubicin vs cisplatin that is ex-
pressed in a wider spectrum of ultrastructural changes
of cell architectonics in MCF-7 cells of different sub-
lines and apoptotic death of higher numbers of cells.
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Copyrigh © Experimenta Oncology, 2010
|
| id | nasplib_isofts_kiev_ua-123456789-138593 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 1812-9269 |
| language | English |
| last_indexed | 2025-11-30T14:46:13Z |
| publishDate | 2010 |
| publisher | Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| record_format | dspace |
| spelling | Yurchenko, O.V. Rusetskaya, N.V. Naleskina, L.A. Chekhun, V.F. 2018-06-19T10:14:06Z 2018-06-19T10:14:06Z 2010 Ultrastructural changes in tumor cells treated with liposomal forms of anticancer drugs / O.V. Yurchenko, N.V. Rusetskaya, L.A. Naleskina, V.F. Chekhun // Experimental Oncology. — 2010. — Т. 32, № 1. — С. 24-28. — Бібліогр.: 27 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/138593 Aim: To determine the main ultrastructural changes in MCF-7 sublines sensitive and resistant to cytotoxic action of anticancer drugs, resulting from the treatment with conventional and liposomal forms of cisplatin and doxorubicin. Methods: Electron microscopy, light microscopy, MTT-test. Results: It has been shown that the phenomenon of drug resistance is associated with complication of ultrastructural organization of cells and more high differentiation by the main cytomorphologic characteristics which promote their resistance to cytotoxic action of anticancer preparations. Cytoarchitectonics of all resistant cells possesses common patterns and doesn’t depend on the particular drugs toward which the resistance has been developed. It has been shown that the cells of the parental form MCF-7 line are more sensitive to cytotoxic action of doxorubicin than to cisplatin. Liposomal forms of anticancer drugs used at the same concentrations that the conventional ones, especially that of doxorubicin, caused more expressed alterations in ultrastructural organization of cells of all studied sublines with dominance of apoptotic processes. Conclusion: Evaluating an effect of equal concentrations of cisplatin and doxorubicin in conventional and liposomal forms, one may conclude on higher cytotoxic action of doxorubicin vs. cisplatin that is expressed in a wider spectrum of ultrastructural changes of cell architectonics in different sublines of MCF-7 cells and higher rate of apoptosis. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Original contributions Ultrastructural changes in tumor cells treated with liposomal forms of anticancer drugs Article published earlier |
| spellingShingle | Ultrastructural changes in tumor cells treated with liposomal forms of anticancer drugs Yurchenko, O.V. Rusetskaya, N.V. Naleskina, L.A. Chekhun, V.F. Original contributions |
| title | Ultrastructural changes in tumor cells treated with liposomal forms of anticancer drugs |
| title_full | Ultrastructural changes in tumor cells treated with liposomal forms of anticancer drugs |
| title_fullStr | Ultrastructural changes in tumor cells treated with liposomal forms of anticancer drugs |
| title_full_unstemmed | Ultrastructural changes in tumor cells treated with liposomal forms of anticancer drugs |
| title_short | Ultrastructural changes in tumor cells treated with liposomal forms of anticancer drugs |
| title_sort | ultrastructural changes in tumor cells treated with liposomal forms of anticancer drugs |
| topic | Original contributions |
| topic_facet | Original contributions |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/138593 |
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