Characteristics of homocysteine-induced multidrug resistance of human MCF-7 breast cancer cells and human A2780 ovarian cancer cells
Aim:To study the influence of homocysteine on the mechanisms of drug resistance formation. Methods: In current study human MCF-7 breast cancer cells and A2780 ovarian cancer cells sensitive to anticancer drugs were used. To access the viability of cells, we applied 3-[4,5-dimethylthiazol-2–1]-2,5-di...
Збережено в:
| Дата: | 2010 |
|---|---|
| Автор: | |
| Формат: | Стаття |
| Мова: | English |
| Опубліковано: |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2010
|
| Назва видання: | Experimental Oncology |
| Теми: | |
| Онлайн доступ: | http://dspace.nbuv.gov.ua/handle/123456789/138589 |
| Теги: |
Додати тег
Немає тегів, Будьте першим, хто поставить тег для цього запису!
|
| Назва журналу: | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| Цитувати: | Characteristics of homocysteine-induced multidrug resistance of human MCF-7 breast cancer cells and human A2780 ovarian cancer cells / N.Yu. Lukyanova // Experimental Oncology. — 2010. — Т. 32, № 1. — С. 10-14. — Бібліогр.: 38 назв. — англ. |
Репозитарії
Digital Library of Periodicals of National Academy of Sciences of Ukraine| id |
irk-123456789-138589 |
|---|---|
| record_format |
dspace |
| spelling |
irk-123456789-1385892018-06-20T03:06:35Z Characteristics of homocysteine-induced multidrug resistance of human MCF-7 breast cancer cells and human A2780 ovarian cancer cells Lukyanova, N.Yu. Original contributions Aim:To study the influence of homocysteine on the mechanisms of drug resistance formation. Methods: In current study human MCF-7 breast cancer cells and A2780 ovarian cancer cells sensitive to anticancer drugs were used. To access the viability of cells, we applied 3-[4,5-dimethylthiazol-2–1]-2,5-diphenyltetrazolium bromide colorimetric assay (MTT-test). Expression of Bcl-2, p-glycoprotein (P-gp), glutathione S-transferase (GST) and E-cadherin was studied by immunocytochemistry. Results: A2780 and MCF-7 cells were treated by homocysteine. It was shown that every next treatment with homocysteine (up to 5th) decreased the sensitivity of A2780 and MCF-7 cells to cytotoxic drugs. Immunocytochemical study of molecular profile of A2780 and MCF-7 cells after long-term cultivation with homocysteine has been carried out and has revealed that such treatment resulted in the induction of Bcl-2, P-gp, GST and E-cadherin expression. This indicates that incubation of studied cells with homocysteine leads to simultaneous induction of expression of drug resistance markers to cisplatin and doxorubicin. Conclusion: Cultivation of MCF-7 and A2780 cells with homocysteine leads to simultaneous development of resistance to doxorubicine and cisplatin. The development of drug resistance is diverse for different drugs and varies among cell lines. 2010 Article Characteristics of homocysteine-induced multidrug resistance of human MCF-7 breast cancer cells and human A2780 ovarian cancer cells / N.Yu. Lukyanova // Experimental Oncology. — 2010. — Т. 32, № 1. — С. 10-14. — Бібліогр.: 38 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/138589 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| institution |
Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| collection |
DSpace DC |
| language |
English |
| topic |
Original contributions Original contributions |
| spellingShingle |
Original contributions Original contributions Lukyanova, N.Yu. Characteristics of homocysteine-induced multidrug resistance of human MCF-7 breast cancer cells and human A2780 ovarian cancer cells Experimental Oncology |
| description |
Aim:To study the influence of homocysteine on the mechanisms of drug resistance formation. Methods: In current study human MCF-7 breast cancer cells and A2780 ovarian cancer cells sensitive to anticancer drugs were used. To access the viability of cells, we applied 3-[4,5-dimethylthiazol-2–1]-2,5-diphenyltetrazolium bromide colorimetric assay (MTT-test). Expression of Bcl-2, p-glycoprotein (P-gp), glutathione S-transferase (GST) and E-cadherin was studied by immunocytochemistry. Results: A2780 and MCF-7 cells were treated by homocysteine. It was shown that every next treatment with homocysteine (up to 5th) decreased the sensitivity of A2780 and MCF-7 cells to cytotoxic drugs. Immunocytochemical study of molecular profile of A2780 and MCF-7 cells after long-term cultivation with homocysteine has been carried out and has revealed that such treatment resulted in the induction of Bcl-2, P-gp, GST and E-cadherin expression. This indicates that incubation of studied cells with homocysteine leads to simultaneous induction of expression of drug resistance markers to cisplatin and doxorubicin. Conclusion: Cultivation of MCF-7 and A2780 cells with homocysteine leads to simultaneous development of resistance to doxorubicine and cisplatin. The development of drug resistance is diverse for different drugs and varies among cell lines. |
| format |
Article |
| author |
Lukyanova, N.Yu. |
| author_facet |
Lukyanova, N.Yu. |
| author_sort |
Lukyanova, N.Yu. |
| title |
Characteristics of homocysteine-induced multidrug resistance of human MCF-7 breast cancer cells and human A2780 ovarian cancer cells |
| title_short |
Characteristics of homocysteine-induced multidrug resistance of human MCF-7 breast cancer cells and human A2780 ovarian cancer cells |
| title_full |
Characteristics of homocysteine-induced multidrug resistance of human MCF-7 breast cancer cells and human A2780 ovarian cancer cells |
| title_fullStr |
Characteristics of homocysteine-induced multidrug resistance of human MCF-7 breast cancer cells and human A2780 ovarian cancer cells |
| title_full_unstemmed |
Characteristics of homocysteine-induced multidrug resistance of human MCF-7 breast cancer cells and human A2780 ovarian cancer cells |
| title_sort |
characteristics of homocysteine-induced multidrug resistance of human mcf-7 breast cancer cells and human a2780 ovarian cancer cells |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2010 |
| topic_facet |
Original contributions |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/138589 |
| citation_txt |
Characteristics of homocysteine-induced multidrug resistance of human MCF-7 breast cancer cells and human A2780 ovarian cancer cells / N.Yu. Lukyanova // Experimental Oncology. — 2010. — Т. 32, № 1. — С. 10-14. — Бібліогр.: 38 назв. — англ. |
| series |
Experimental Oncology |
| work_keys_str_mv |
AT lukyanovanyu characteristicsofhomocysteineinducedmultidrugresistanceofhumanmcf7breastcancercellsandhumana2780ovariancancercells |
| first_indexed |
2025-07-10T06:07:38Z |
| last_indexed |
2025-07-10T06:07:38Z |
| _version_ |
1837239017457844224 |
| fulltext |
10 Experimental Oncology 32, 10–14, 2010 (March)
Drug resistance is a complex and comprehensive
problem of modern oncology that determines a num-
ber of failures during therapy of cancer patients. The
study of mechanisms of the development of resistance
to cancer preparations is important for understanding
the way of correction of tumor cell phenotype toward
elevation of its sensitivity to chemotherapy.
Due to the development of resistance, cells acquire
new properties that are reflected at morphological level
as well as on the change of their molecular, phenotypic
and biochemical patterns [1–8]. That’s why compara-
tive study of biological patterns of sensitive cell and its
resistant analog will help to identify the mechanisms
of drug resistance development.
Cultivated lines of resistant cells of different his-
togenesis may serve as a convenient model for such
research. The method of formation of drug resistance,
a main method of experimental oncology, is grounded
on prolonged cultivation of tumor cells in the medium
with gradually increasing concentrations of anticancer
preparations [9]. However, the method is associated
with certain difficulties. Firstly, this process requires
significant time period; for example, achievement
of resistance to doxorubicin in human MCF-7 breast
cancer cell line requires at least 4–5 months (resis-
tance level 16), to cisplatin — 7–8 months (resistance
level 4), while the development of resistance to doxoru-
bicin in human A2780 ovarian cancer cell line occupies
11–12 months (resistance level 6), and to cisplatin —
6.5–8 months (resistance level 8). Secondly, drug
resistance in human tumor is often characterized by
cross-resistance to two and more anticancer prepa-
rations, while the mentioned method allows achieve
the resistance only to one anticancer preparation at
the time. Thirdly, further cultivation of resistant cells
without addition of anticancer preparations leads to
significant decrease of resistance level [9].
It is known that in blood plasma of patients with
tumors of different localization elevated level of homo-
cysteine could be detected, and in some cases it may
be explained by the development of drug resistance.
Homocysteine is a sulfur-containing amino acid that
is not present in natural proteins but is an intermediate
product of exchange between amino acids methionine
and cysteine [10–14]. According to the data of nume-
rous studies [15–22], elevated homocysteine content
is directly linked to deficiency in methyl groups what in
turn leads to hypomethylation. It is known that distur-
bance in DNA methylation map plays a role in regula-
tion of expression of genes [20–25], the protein prod-
ucts of which determine different mechanisms of drug
resistance formation: functioning of transport systems
(genes mdr1 [24–28], mrp1 [27–29], lrp [28, 29])
that results in decreased intracellular accumulation of
cytostatic preparations; altered proteins — apoptosis
regulators (genes p53 [29], bcl-2 [30, 31]); elevated
activity of detoxification systems (genes GSTπ [31],
MT [31–33]), system of DNA-adducts reparation (gene
MGMT [33]) that appear during interaction of a number
of anticancer preparations with DNA molecule, etc. So,
the study of influence of elevated concentrations of ho-
mocysteine on the mechanisms of formation of drug
resistance allows reveal the initial chains involved in
the development of this process.
MATERIALS AND METHODS
Parental human MCF-7 breast cancer cells and
A2780 ovarian cancer cells sensitive to anticancer
CHARACTERISTICS OF HOMOCYSTEINE-INDUCED MULTIDRUG
RESISTANCE OF HUMAN MCF-7 BREAST CANCER CELLS
AND HUMAN A2780 OVARIAN CANCER CELLS
N.Yu. Lukyanova*
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv 03022, Ukraine
Aim: To study the influence of homocysteine on the mechanisms of drug resistance formation. Methods: In current study human
MCF-7 breast cancer cells and A2780 ovarian cancer cells sensitive to anticancer drugs were used. To access the viability of cells,
we applied 3-[4,5-dimethylthiazol-2–1]-2,5-diphenyltetrazolium bromide colorimetric assay (MTT-test). Expression of Bcl-2,
p-glycoprotein (P-gp), glutathione S-transferase (GST) and E-cadherin was studied by immunocytochemistry. Results: A2780 and
MCF-7 cells were treated by homocysteine. It was shown that every next treatment with homocysteine (up to 5th) decreased the sen-
sitivity of A2780 and MCF-7 cells to cytotoxic drugs. Immunocytochemical study of molecular profile of A2780 and MCF-7 cells
after long-term cultivation with homocysteine has been carried out and has revealed that such treatment resulted in the induction
of Bcl-2, P-gp, GST and E-cadherin expression. This indicates that incubation of studied cells with homocysteine leads to simul-
taneous induction of expression of drug resistance markers to cisplatin and doxorubicin. Conclusion: Cultivation of MCF-7 and
A2780 cells with homocysteine leads to simultaneous development of resistance to doxorubicine and cisplatin. The development
of drug resistance is diverse for different drugs and varies among cell lines.
Key Words: MCF-7 cells, A2780 cells, cisplatin, doxorubicin, drug resistance, homocysteine, immunocytochemistry.
Received: January 20, 2010.
*Correspondence: Fax: +38 (044) 258-16-56
E-mail: oncom@onconet.kiev.ua
Abbreviations used: GST — glutathione S-transferase; MAbs —
monoclonal antibodies; MTT — 3-[4,5-dimethylthiazol-2–1]-2,5-
diphenyltetrazolium bromide; P-gp — p-glycoprotein.
Exp Oncol 2010
32, 1, 10–14
ORIGINAL CONTRIBUTIONS
Experimental Oncology 32, 10–14, 2010 (March) 11
drugs (cisplatin and doxorubicin) were studied. Cis-
platin and doxorubicin were from Ebewe, Austria. The
cells of both lines were cultured in modified Dulbecco
ISCOV medium (Sigma, Germany) supplemented with
10% of fetal calf serum (Sangva, Ukraine) at 37 °C
in humidified 5% CO2. Cells were cultured for 24 h, and
then homocysteine (Sigma, Germany) was added to
culture medium at the concentrations of 50 or 100 mM.
Incubation with homocysteine lasted for 72 h, then the
cells were passaged, the cycle of abovementioned
treatment was repeated 10 times, and then the cells
were cultured for 3 months without homocysteine. The
control cells of both lines were cultured without addition
of homocysteine to culture medium.
Cytotoxicity test was performed after 1, 3, 5, and
10 cycles of homocysteine treatment and after 3-months
period of homocysteine-free cultivation using 3-[4,5-di-
methylthiazol-2–1]-2,5-diphenyltetrazolium bromide
(Sigma, Germany) in standard MTT-test [34].
Expression of surface and intracellular protein
(apoptosis regulator Bcl-2), proteins associated with
drug resistance (glycoprotein (P-gp) and glutathione
S-transferase (GST)), molecules of intercellular adhe-
sion (E-cadherins) was studied by immunocytochemi-
cal peroxydase-antiperoxydase (PAP) method using
murine monoclonal antibodies (MAbs), secondary
rabbit antibodies against mice immunoglobulins, and
complex of MAbs against peroxydase with raddish
peroxidase, and also EnVision visualization system
(DakoCytomation, Denmark) [2, 35].
RESULTS AND DISCUSSION
It has been shown that 72 h incubation of ovarian can-
cer cells of A2780 line with homocysteine resulted in the
decrease of their sensitivity to the action of cisplatin by
2.5-fold, and to doxorubicin — by 2-fold, compared to the
control cells, while 3rd treatment with homocysteine — by
2.7-fold and 2.2-fold decrease, and after 5-th — 4.5-fold
and 2.7 decrease, respectively. It’s necessary to note that
further cultivation of the cells with homocysteine didn’t
lead to elevation of their drug resistance level.
An acquirement of drug resistant phenotype in
A2780 cells treated for long time with elevating concen-
trations of cisplatin occurs via antiapoptotic program [2]
and is accompanied by an appearance of expression of
Bcl-2 oncoprotein and GST — the protein responsible
for intracellular detoxification (Fig. 1) [2]. Also, develop-
ment of resistance to doxorubicin in these cells occurs
via induction of P-gp and E-cadherin expression (see
Fig. 1) [2]. So, development of resistance to cisplatin
and doxorubicin in cells of this histogenesis occurs via
different mechanisms. That’s why immunocytochemical
study of molecular profile of A2780 cells after long-term
cultivation with homocysteine has been carried out, and
has revealed that such treatment resulted in the induc-
tion of Bcl-2, P-gp, GST and E-cadherin expression
(Fig. 2). This indicates that incubation of A2780 cells
with homocysteine leads to simultaneous induction
of expression of drug resistance markers which are
common in cells resistant to cisplatin and doxorubicin,
and intensity of immunocytochemical reaction (i. e.
higher level of markers expression) elevates along with
increasing number of passages.
a
b
с
d
Fig. 1. Bcl-2 (a) and GST (b) expression in А2780/DDP cells,
P-gp (c) and E-cadherin (d) expression in A2780/Dox cells
Incubation of MCF-7 cells with homocysteine for
72 h resulted in the decrease of cells sensitivity to
doxorubicin by 2.5-fold and to cisplatin — by 1.5-fold,
compared to the control, while after third introduction
of homocysteine into the culture medium the degree of
MCF-cells resistance was equal to 3, and to cisplatin —
12 Experimental Oncology 32, 10–14, 2010 (March)
1.7, and after the fifth treatment these values were
equal to 5.0 and 2.5 respectively. Further cultivation
of MCF-7 cells with homocysteine had no additional
impact on their resistance to mentioned drugs.
a
b
с
d
Fig. 2. Bcl-2 (a), P-gp (b), GST (c) and E-cadherin (d) expression
in А2780 cells with homocysteine-induced resistance
It is known that the development of drug resistance
in MCF-7 cells upon action of elevating concentrations
of cisplatin and doxorubicin is accompanied by the
increase of cell adhesion (Fig. 3) [36]. Development
of resistance to cisplatin in MCF-7 cells occurs via an-
tiapoptotic mechanisms (decreased Bcl-2 expression)
and the system of intracellular detoxification (GST) [36],
while doxorubicin-resistant MCF-7 cells acquire such
properties via MDR-dependent mechanisms (elevated
P-gp expression) (see Fig. 3).
a
b
с
d
Fig. 3. Bcl-2 (a), GST (b) and E-cadherin (c) expression
in MCF-7/DDP cells, P-gp (d) expression in MCF-7/Dox cells
Immunocytochemical study has demonstrated that
incubation of MCF-7 cells with homocysteine resulted
in the induction of P-gp, GST and E-cadherin expres-
sion and significant decrease of Bcl-2 (Fig. 4). So, our
Experimental Oncology 32, 10–14, 2010 (March) 13
data have shown that alteration of molecular profile of
MCF-7 cells upon the action of homocysteine reflects
an involvement of both mechanisms responsible for the
development of resistance to cisplatin and doxorubicin.
a
b
с
d
Fig. 4. Bcl-2 (a), GST (b), E-cadherin (c) and P-gp (d) expression
in MCF-7 cells with homocysteine-induced resistance
It has been shown that further three months long
cultivation of drug resistant cells in the medium without
homocysteine doesn’t lead to decrease of resistance
level.
So, cultivation of MCF-7 and A2780 cells with
homocysteine leads to simultaneous development
of resistance to doxorubicin and cisplatin. Increase
of homocysteine concentration in culture medium
over certain critical level causes maximal tension of
systems of its utilization that can’t release the cell from
its excess, what results in total genome demethylation
upon conditions of deficiency of methyl groups donors,
and consequently leads to elevation of activity of the
majority of genes thus crea ting the grounds of tumor
cell genetic instability.
Summarizing abovementioned, one should note
that the creation of in vitro hyperhomocysteinemia
model allows in 2–3 weeks receive cell strains with
cross-resistance to doxorubicin and cisplatin. The
recent studies have shown that the development of
multidrug resistance phenotype involves a number
of mechanisms and activation of respective genes;
altered P-gp, GST and E-cadherin expression are di-
rectly linked to DNA methylation [13, 14, 37, 38]. From
other hand, hypomethylation of DNA may be caused
by disturbed metabolism of folic acids that leads to
hyperhomocysteinemia.
Along with this, the mechanisms of formation of
drug resistance upon elevated homocysteine level are
far from being clear yet. Such process is associated
with altered DNA methylation map (its hypomethyl-
ation) due to deficiency of methyl groups that appears
as a result of compensatory elevation of activity of the
systems of homocysteine utilization in response to its
increased concentration in intracellular medium, and,
possibly, due to inhibition of functions of DNA-methyl-
transferase-1 via deficiency of its substrate. Further
studies of homocysteine-induced multidrug resistance
in MCF-7 and A2780 cells will be required for under-
standing the ways to overcome natural and acquired
drug resistance.
ACKNOWLEDGMENTS
Author gratefully acknowledges Head of Depart-
ment of Mechanisms of Anticancer Therapy
of R.E. Kavetsky Institute of Experimental Pathology,
Oncology and Radiobiology, academician V.F. Chekhun
and collaborators for valuable advices and comments.
REFERENCES
1. Chekhun VF, Kulik GI, Yurchenko OV, et al. Role
of DNA hypomethylation in the development of the resistance
to doxorubicin in human MCF-7 breast adenocarcinoma cells.
Cancer Letters 2006; 231: 87–93.
2. Chekhun VF, Lukyanova NYu, Yurchenko OV, et al. The role
of expression of the components of proteome in the formation
of molecular profile of human ovarian carcinoma A2780 cells
sensitive and resistant to cisplatin. Exp Oncol 2005; 27: 191–5.
3. Chekhun VF, Shishova YuV. Current opinion on development
of tumor drug resistance. Oncology 2000; 2: 11–5 (In Russian).
4. Kurpeshev OK, Tsyb AF, Mardynsky YuS, et al. Mecha-
nisms of development and overcoming of tumor resistance. Rus
J Oncol 2002; 6: 48–52 (In Russian).
5. Chekhun VF, Ganina KP, Kulik GI, et al. Impact of tu-
mor drug resistance phenotype on the dynamics of cisplatin-
induced changes in chromatin structure of peripherial blood
14 Experimental Oncology 32, 10–14, 2010 (March)
limphocytes nuclei from rats with Guerin carcinoma. Cytology
and Genetics 2000; 34: 17 (In Russian).
6. Li DJ, Zhang YZ, Zhang DH. Activity of telomerase
and extracellular regulated protein kinases in parental and drag
resistant cells of leukemia and ovarian cancer. Zhongguo Shi Yan
Xue Ye Xue Za Zhi 2004; 12: 304–8.
7. Yoon KA, Ku JL, Yang JO, et al. Telomerase activity,
expression of Bcl-2 and cell cycle regulation in doxorubicin resis-
tant gastric carcinoma cell lines. Int J Mol Med 2003; 11: 343–8.
8. Arts HJG, Katsaros D, Vries EGE, et al. Drug resis-
tance associated markers P-glycoprotein, multidrug resistance-
associated protein 1, multidrug resistance-associated protein 2,
and lung resistance protein as prognostic factors in ovarian
carcinoma. Clin Cancer Res 1999; 5: 2798–805.
9. Chekhun VF, Shishova YuV, Yurchenko OV, et al. Synergy
between cisplatin and IPO-4 monoclonal antibodies against
human epidermoid carcinoma КВ cells. Exp Oncol 1998; 20:
210–6 (In Russian).
10. Miller AL, Kelly GS. Homocysteine metabolism: nut-
ritional modulation and impact on health and disease. Alt Med
Rev 1997; 2: 234–54.
11. McCully KS. The biomedical significance of homocys-
teine. J Sci Expl 2001; 15: 5–20.
12. Shevchenko OP. Homocysteine — a new risk factor
in atherosclerosis and thrombosis (lecture). Clinical Labora-
tory Diagnostics 2004; 10: 25–31 (In Russian).
13. den Heijer M, Koster T, Blom HJ, et al. Hyperhomo-
cysteinemia as a risk factor for deep-vein thrombosis. NEJM
1996; 334: 759–62.
14. Rassmusen К, Moller J. Total homocesteine measure-
ment in clinical practice. Ann Clin Biochem 2000; 37: 627–48.
15. Hultberg B, Andersson A, Isaksson A. The cell-damag-
ing effects of low amounts of homocysteine and copper ions in
human cell line cultures are caused by oxidative stress. Toxicol
1997; 123: 33–40.
16. Pentyuk OO, Il’chenko OV, Shevchuk SV, et al. Study
of homocysteine concentrations in biological fluids using
HPLC method. Works Podillya Academy Fundamental Ap-
plied Sci 2000; 2: 54–60 (In Ukrainian).
17. Brenner B. Thrombophilia and cancer in the pathogenesis
of arterial thrombosis. J Clin Basic Cardiol 2000; 3: 89–90.
18. Zhu BT. Medical hypothesis: hyperhomocysteinemia
is a risk factor for estrogen-induced hormonal cancer. J Oncol
2003; 22: 499–508.
19. Gvozdev VA. Regulation of gene activity as a result
of DNA chemical modification (methylation). Soros Educ J
1999; 10: 11–7 (In Russian).
20. Robertson KD, Jones PA. DNA methylation: past,
pre sent and future directions. Carcinogenesis 2000; 21: 461–7.
21. Robertson KD, Wolffe AP. DNA methylation in health
and disease. Nature Rev Genetics 2000; 1: 11–9.
22. Zingg J-M, Jones PA. Genetic and epigenetic aspects
of DNA methylation on genome expression, evolution, muta-
tion and carcinogenesis. Carcinogenesis 1997; 18: 869–82.
23. Costello JF, Plass C. Methylation matters. J Med Genet
2001; 38: 285–303.
24. Kuranaga N, Shinomiya N, Mochizuki H. Long-term
cultivation of colorectal carcinoma cells with anti-cancer
drugs induces drug resistance and telomere elongation: an
in vitro study. BMC Cancer 2001; 1: 10–8.
25. Enokida H, Shiina H, Igawa M, et al. CpG hyper-
methylation of MDR1 gene contributes to the pathogenesis
and progression of human prostate cancer. Cancer Res 2004;
64: 5956–62.
26. David GL, Yegnasubramanian S, Kumar A, et al.
MDR1 promoter hypermethylation in MCF-7 human breast
cancer cells: changes in chromatin structure induced by treat-
ment with 5-Aza-cytidine. Cancer Biol Ther 2004; 3: 540–8.
27. Perkins C, Kim CN, Fang G, et al. Arsenic induces
apoptosis of multidrug-resistant human myeloid leukemia
cells that express Bcr-Abl or overexpress MDR, MRP, Bcl-2,
or Bcl-xL. Blood 2000; 95: 1014–22.
28. Leith CP, Kopecky KJ, Chen IM, et al. Frequency
and clinical significance of the expression of the multidrug
resistance proteins MDR1/P-glycoprotein, MRP1, and LRP
in acute myeloid leukemia: a Southwest Oncology Group
Study. Blood 1999; 94: 1086–99.
29. Oudard S, Levalois C, Andrieu JM, et al. Expression
of genes involved in chemoresistance, proliferation and apop-
tosis in clinical samples of renal cell carcinoma and correlation
with clinical outcome. Anticancer Res 2002; 22: 121–8.
30. Kim HH, Park CS. Lipotropes regulate bcl-2 gene ex-
pression in the human breast cancer cell line, MCF-7. In Vitro
Cell Dev Biol Anim 2002; 38: 205–7.
31. Ding S, Gong BD. Methylation profile of the promoter
CpG islands of 14 “drug-resistance” genes in hepatocellular
carcinoma. World J Gastroenterol 2004; 10: 3433–40.
32. Zhao CQ, Young MR, Diwan BA, et al. Association of
arsenic-induced malignant transformation with DNA hypo-
methylation and aberrant gene expression. Proc Natl Acad Sci
USA 1997; 94: 10907–12.
33. dit Faute MA, Laurent L, Ploton D, et al. Distinctive al-
teration of invasiveness, drug resistance and cell-cell organization
in 3D-cultires of MCF-7, a human breast cancer cell line, and its
multidrug resistance variant. Clin Exp Metastasis 2002; 19: 161–8.
34. Ni J, Hollander D. Application of the MTT-assay to
functional studies of mouse intestinal intraepithelial lympho-
cytes. J Clin Lab Anal 1996; 10: 42–52.
35. Yurchenko O, Shlapatska L, Skryma M, et al. Immu-
nohistochemical studies of CD150 expression in some human
tumors. Exp Oncol 2003; 25: 186–90.
36. Lukyanova NYu, Rusetskaya NV, Tregubova NA, et al.
Molecular profile and cell cycle in MCF-7 cells resistant to
cisplatin and doxorubicin. Exp Oncol 2009; 31: 87–92.
37. Hajjar KA. Homocysteine: a sulph’rous fire. J Clin
Invest 2001; 107: 663–4.
38. Jakubowski H. Homocysteine is a protein amino acid
in humans. J Biol Chem 2002; 227: 30425–8.
Copyright © Experimental Oncology, 2010
|