Growth suppression activity of bradykinin antagonists in glioma cells
The present study was Aimed at analyzing the effect of bradykinin (BK) antagonists on proliferation of the human glioblastoma cells U373. Methods. MTT-based cell proliferation assay. Results. BKM-570 revealed a significant antiproliferative activity in the U373 cells with LC50 3,8 M. Conclusions. Th...
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| Опубліковано в: : | Вiopolymers and Cell |
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| Дата: | 2014 |
| Автори: | , , , , |
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| Мова: | Англійська |
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Інститут молекулярної біології і генетики НАН України
2014
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| Цитувати: | Growth suppression activity of bradykinin antagonists in glioma cells / S.S. Avdieiev, L. Gera, R. Hodges, Y.S. Vassetzky, V.M. Kavsan // Вiopolymers and Cell. — 2014. — Т. 30, № 1. — С. 77-79. — Бібліогр.: 7 назв. — англ. |
Репозитарії
Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1859629037186449408 |
|---|---|
| author | Avdieiev, S.S. Gera, L. Hodges, R. Vassetzky, Y.S. Kavsan, V.M. |
| author_facet | Avdieiev, S.S. Gera, L. Hodges, R. Vassetzky, Y.S. Kavsan, V.M. |
| citation_txt | Growth suppression activity of bradykinin antagonists in glioma cells / S.S. Avdieiev, L. Gera, R. Hodges, Y.S. Vassetzky, V.M. Kavsan // Вiopolymers and Cell. — 2014. — Т. 30, № 1. — С. 77-79. — Бібліогр.: 7 назв. — англ. |
| collection | DSpace DC |
| container_title | Вiopolymers and Cell |
| description | The present study was Aimed at analyzing the effect of bradykinin (BK) antagonists on proliferation of the human glioblastoma cells U373. Methods. MTT-based cell proliferation assay. Results. BKM-570 revealed a significant antiproliferative activity in the U373 cells with LC50 3,8 M. Conclusions. The antiproliferative properties of BK antagonists were shown in vitro using the glioma cells. Further investigations of the molecular mechanisms of their action and pre-clinical studies on animal models are needed for the evaluation of these compounds as new anti-cancer drugs.
Мета цього дослідження полягала в аналізі впливу антагоністів брадикініну на проліферацію клітин гліобластоми людини U373. Методи. МТТ аналіз пролиіферації клітин. Результати. BKM-570 продемонстрував значну антипроліферативну активність у клітинах U373 (LC50 3,8 мкМ). Висновки. Антипроліферативні властивості антагоністів брадикініну показано з використанням моделі гліоми in vitro. Подальші дослідження молекулярних механізмів дії, а також доклінічні випробування із застосуванням тваринних моделей необхідні для оцінювання зазначених сполук як нових протиракових препаратів.
Цель данного исследования состояла в анализе влияния антагонистов брадикинина на пролиферацию клеток глиобластомы человека U373. Методы. МТТ анализ пролиферации клеток. Результаты. BKM-570 продемонстрировал значительную антипролиферативную активность в клетках U373 (LC50 3,8 мкМ). Выводы. Антипролиферативные свойства антагонистов брадикинина показаны с использованием модели глиомы in vitro. Дальнейшие исследования молекулярных механизмов действия, а также доклинические испытания с применением животных моделей необходимы для оценки этих соединений в качестве новых противораковых препаратов.
|
| first_indexed | 2025-12-07T13:09:07Z |
| format | Article |
| fulltext |
UDC 577.21 : 016-006.04
Growth suppression activity of bradykinin
antagonists in glioma cells
S. S. Avdieiev1, L. Gera2, R. Hodges2, Y. S. Vassetzky3, V. M. Kavsan1
1State Key Laboratory of Molecular and Cellular Biology
Institute of Molecular Biology and Genetics, NAS of Ukraine
150, Akademika Zabolotnoho Str., Kyiv, Ukraine 03680
2University of Colorado Denver
Anschutz Medical Campus, Aurora CO 80045, USA
3CNRS UMR8126, Paris-Sud University, Gustave Roussy Institute
114, rue Edouard Vaillant, 94805 Villejuif Cedex-France
Conventional glioblastoma treatment still gives very modest results, thus development of the new treatment
modalities is desperately needed for these disease.The present study was aimed at analyzing the effect of brady-
kinin (BK) antagonists on proliferation of the human glioblastoma cells U373. Methods. MTT-based cell prolife-
ration assay. Results. BKM-570 revealed a significant antiproliferative activity in the U373 cells with LC
50
3,8
mM. Conclusions. The antiproliferative properties of BK antagonists were shown in vitro using the glioma cells.
Further investigations of the molecular mechanisms of their action and pre-clinical studies on animal models are
needed for the evaluation of these compounds as new anti-cancer drugs.
Keywords: bradykinin antagonists, glioma cells, antiproliferative activity.
Introduction. Glioblastoma is the most common and
lethal form of the central nervous system tumors, and is
known to be highly therapy resistant. Development of
the new treatment modalities is desperately needed for
these diseases.
Nonapeptide bradykinin (BK) is known to stimula-
te cancer cells growth [1] as well as their migration and
invasion by inducing the activity of matrix metallopro-
tease (MMP) [2]. BK is linked to the formation of new
blood vessels by stimulating the release of vascular en-
dothelial growth factor (VEGF) [2]. These activities
operate together to promote strongly the growth and in-
vasive properties of certain tumor types, especially glio-
mas, thereby place BK in an ideal position for the gene-
rating of anti-cancer drugs.
The BK antagonists with impressive inhibition of
the human cancer cell lines and the mouse tumor xeno-
grat growth have been developed [3]. Despite the inten-
sive study of these compounds, there are no published
data about their testing on the glioblastoma cell lines.
Recently, it has been shown that BK acts through a bra-
dykinin receptor 2 (B2R) as a chemoattractant guiding
the glioma cells toward blood vessels in the rat brain
slices [4].
Thus, B2R antagonist emerges as an attractive the-
rapeutic agent for glioma patients.
It has been reported that anti-angiogenesis and anti-
matrix metalloproteases (MMP) activities are impor-
tant components of the excellent in vivo anti-cancer ac-
tivity of BK anatagonists. These substances offer ad-
vantages of combination therapy in one compound.
These promising multitargeted anti-cancer compounds
selectively stimulate apoptosis in cancers and also in-
hibit both angiogenesis and MMP action in treated lung
and prostate tumors in nude mice.
Here we present that the BK antagonist BKM-570
possesses a high antiproliferative activity in the human
glioblastoma cells U373. The obtained results demonst-
77
ISSN 0233–7657. Biopolymers and Cell. 2014. Vol. 30. N 1. P. 77–79 doi: http://dx.doi.org/10.7124/bc.000883
Ó Institute of Molecular Biology and Genetics, NAS of Ukraine, 2014
rate that BKM-570 exhibits the anti-cancer activity.
This work forms a basis for the pre-clinical studies using
animal models for the evaluation of these compounds
as new anti-cancer drugs.
Materials and methods. Cell proliferation assay.
The U373 cells (obtained from R. E. Kavetskogo Insti-
tute of experimental pathology, oncology and radiobio-
logy, NAS of UkraineU) were seeded in triplicates into
96 well plates at density 3 × 103 cells/well and were grown
in complete DMEM («PAA», Germany) in an environ-
ment of 95 % air/5 % CO2.
The drugs were applied at final concentration of
0.01, 0.1, 1, 10, and 100 µM, which were reached by a
serial dilution method. The cell proliferation was mea-
sured using 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl-
tetrazolium bromide (MTT) («Sigma», USA) after 72 h
of cultivation.
Results and discussion. The cancer cells are charac-
terized by an increased proliferation rate. To analyze the
antiproliferative effect of the BK antagonists, we used
the human glioblastoma cells U373. The MTT assay was
employed to determine the growth-suppression effect
of the tested compounds.
Based on the cytotoxicity test data, the LC50 para-
meter was calculated (molar concentration of com-
pound leading to 50 % cell death as compared to a
control group treated with DMSO).
The non-peptide BK antagonist BKM-570 and its
derivative BKM-1800 were enrolled in this study. It
was found that BKM-570 revealed a significant growth
suppressor activity in the U373 cells in dose-dependent
manner after the addition to the culture medium (Figu-
re, A). LC50 of BKM-570 was 3,8 mM, while LC50 of
BKM-1800 was 25,8 mM.
The obtained results were in accordance with those
previously described by Stewart et al. [5]: BKM-570
was the leader compound both in vitro (LC50 1,8 mM on
the small-cell lung cancer (SCLC) cells) and in vivo (91
% inhibition of the tumor xenograf growth in mice).
Our assays revealed much lower activity of BKM-1800,
in contrast to the data published previously by Gera et
al. (LC50 1,7 mM on the SCLC cells in vitro and 78 % of
PC3 prostate cancer growth inhibition in vivo) [6].
Thus, the cytotoxic activity of these compounds
seems to depend on the specificity of each cell line
tested.
Conclusions. In summary, we have shown that
BKM-570 represses the glioblastoma cells growth and is
a promising compound for the in vivo studies as a poten-
tial anti-cancer agent.
Funding. This work was supported in part by State
Agency for Science, Innovations and Informatization
of Ukraine in frames of the project F33.4/001 «Identi-
fication of promising molecular biomarkers for moni-
toring of human neurodegenerative and oncological di-
seases» and the State Fund of Fundamental Research
project F 46/366-2013.
Àíòèïðîë³ôå ðà òèâ íà àê òèâí³ñòü àí òà ãîí³ñò³â
áðà äèê³í³íó ó êë³òè íàõ ãë³îìè
Ñ. Ñ. Àâäåºâ, Ë. Ãåðà, Ð. Õîä ãåñ, ª. Ñ. Âàñ åöü êèé, Â. Ì. Êàâ ñàí
Ðå çþ ìå
Ñòàí äàð òíà òå ðàï³ÿ ãë³îá ëàñ òî ìè äຠäóæå íå çíà÷í³ ðå çóëü òà -
òè. Òà êèì ÷è íîì, ðîç ðîá êà íî âèõ ìå òîä³â º âêðàé íå îáõ³äíîþ äëÿ
åôåê òèâ íî ãî ë³êó âàí íÿ öüî ãî çà õâî ðþ âàí íÿ. Ìåòà ïðåäñòàâ ëå íî -
ãî äîñë³äæåí íÿ ïî ëÿ ãà ëà â àíàë³ç³ âïëè âó àí òà ãîí³ñò³â áðà äèê³-
í³íó íà ïðîë³ôå ðàö³þ êë³òèí ãë³îá ëàñ òî ìè ëþ äè íè U373. Ìå òî -
äè. ÌÒÒ àíàë³ç ïðî ëè³ôå ðàö³¿ êë³òèí. Ðå çóëü òà òè. BKM- 570 ïðî -
äå ìî íñòðóâàâ çíà÷ íó àí òèï ðîë³ôå ðà òèâ íó àê òèâí³ñòü ó êë³òè-
íàõ U373 (LC50 3,8 ìêÌ). Âèñ íîâ êè. Àíòèïðîë³ôå ðà òèâí³ âëàñ òè -
âîñò³ àí òà ãîí³ñò³â áðà äèê³í³íó ïî êà çà íî ç âè êî ðèñ òàí íÿì ìî äåë³
ãë³îìè in vitro. Ïî äàëüø³ äîñë³äæåí íÿ ìî ëå êó ëÿð íèõ ìå õàí³çì³â
䳿, à òà êîæ äîêë³í³÷í³ âèï ðî áó âàí íÿ ³ç çà ñòî ñó âàí íÿì òâà ðèí -
íèõ ìî äå ëåé íå îáõ³äí³ äëÿ îö³íþ âàí íÿ çà çíà ÷å íèõ ñïî ëóê ÿê íî âèõ
ïðî òè ðà êî âèõ ïðå ïà ðàò³â.
AVDIEIEV S. S. ET AL.
78
Drug c once ntration, µ M
C
ul
tu
re
gr
o
w
th
,%
0.01 0.1 1 10 100
0
20
40
60
80
100
1
2
Effect of BK antagonists on U373 cells growth. U373 cells were cul-
tured in the absence (vehicle control) or in the presence of increasing
doses of BKM-570 (1) or BKM-1800 (2) for 72 h. Cells viability was
analyzed by MTT assay. Data are expressed as the percentage of growth
compared to vehicle control (100 %). Each point represents the mean
of three experiments performed in triplicate
Êëþ ÷îâ³ ñëî âà: àí òà ãîí³ñòè áðà äèê³í³íó, êë³òèíè ãë³îìè, àíòè-
ïðîë³ôå ðà òèâ íà àê òèâí³ñòü.
Àíòèïðîëèôåðàòèâíàÿ àê òèâ íîñòü àí òà ãî íèñ òîâ áðà äè êè íè íà
â êëåò êàõ ãëè î ìû
Ñ. Ñ. Àâäååâ, Ë. Ãåðà, Ð. Õîä ãåñ, Å. Ñ. Âàñ åö êèé, Â. Ì. Êàâ ñàí
Ðå çþ ìå
Ñòàí äàð òíàÿ òå ðà ïèÿ ãëè îá ëàñ òî ìû äàåò î÷åíü íå çíà ÷è òåëü-
íûå ðå çóëü òà òû. Òà êèì îá ðà çîì, ðàç ðà áîò êà íî âûõ ìå òî äîâ êðàé-
íå íå îá õî äè ìà äëÿ ýô ôåê òèâ íî ãî ëå ÷å íèÿ ýòî ãî çà áîëåâà íèÿ. Öåëü
äàí íî ãî èñ ñëå äî âà íèÿ ñî ñòî ÿ ëà â àíà ëè çå âëè ÿ íèÿ àí òà ãî íèñ òîâ
áðà äè êè íè íà íà ïðî ëè ôå ðà öèþ êëå òîê ãëè îá ëàñ òî ìû ÷å ëîâåêà
U373. Ìå òî äû. ÌÒÒ àíà ëèç ïðî ëè ôå ðà öèè êëåòîê. Ðå çóëü òà òû.
BKM-570 ïðî äå ìî íñòðè ðî âàë çíà ÷è òåëü íóþ àí òèï ðî ëè ôå ðà òèâ-
íóþ àê òèâ íîñòü â êëåò êàõ U373 (LC50 3,8 ìêÌ). Âû âî äû. Àíòè-
ïðî ëè ôå ðà òèâ íûå ñâî éñòâà àí òà ãî íèñ òîâ áðà äè êè íè íà ïî êà çà -
íû ñ èñ ïîëü çî âà íè åì ìî äå ëè ãëè î ìû in vitro. Äàëü íåé øèå èñ ñëå äî -
âà íèÿ ìî ëå êó ëÿð íûõ ìå õà íèç ìîâ äå éñòâèÿ, à òàê æå äîê ëè íè ÷åñ-
êèå èñ ïû òà íèÿ ñ ïðè ìå íå íè åì æè âîò íûõ ìî äå ëåé íå îá õî äè ìû
äëÿ îöåí êè ýòèõ ñî å äè íå íèé â êà ÷åñ òâå íî âûõ ïðî òè âî ðà êî âûõ
ïðå ïà ðà òîâ.
Êëþ ÷å âûå ñëî âà: àí òà ãî íèñ òû áðà äè êè íè íà, êëåò êè ãëè î ìû,
àíòèï ðî ëè ôå ðà òèâ íàÿ àê òèâ íîñòü.
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Received 15.07.13
79
GROWTH SUPPRESSION ACTIVITY OF BRADYKININ ANTAGONISTS IN GLIOMA CELLS
|
| id | nasplib_isofts_kiev_ua-123456789-153733 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 0233-7657 |
| language | English |
| last_indexed | 2025-12-07T13:09:07Z |
| publishDate | 2014 |
| publisher | Інститут молекулярної біології і генетики НАН України |
| record_format | dspace |
| spelling | Avdieiev, S.S. Gera, L. Hodges, R. Vassetzky, Y.S. Kavsan, V.M. 2019-06-14T14:45:09Z 2019-06-14T14:45:09Z 2014 Growth suppression activity of bradykinin antagonists in glioma cells / S.S. Avdieiev, L. Gera, R. Hodges, Y.S. Vassetzky, V.M. Kavsan // Вiopolymers and Cell. — 2014. — Т. 30, № 1. — С. 77-79. — Бібліогр.: 7 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.000883 https://nasplib.isofts.kiev.ua/handle/123456789/153733 577.21 : 016-006.04 The present study was Aimed at analyzing the effect of bradykinin (BK) antagonists on proliferation of the human glioblastoma cells U373. Methods. MTT-based cell proliferation assay. Results. BKM-570 revealed a significant antiproliferative activity in the U373 cells with LC50 3,8 M. Conclusions. The antiproliferative properties of BK antagonists were shown in vitro using the glioma cells. Further investigations of the molecular mechanisms of their action and pre-clinical studies on animal models are needed for the evaluation of these compounds as new anti-cancer drugs. Мета цього дослідження полягала в аналізі впливу антагоністів брадикініну на проліферацію клітин гліобластоми людини U373. Методи. МТТ аналіз пролиіферації клітин. Результати. BKM-570 продемонстрував значну антипроліферативну активність у клітинах U373 (LC50 3,8 мкМ). Висновки. Антипроліферативні властивості антагоністів брадикініну показано з використанням моделі гліоми in vitro. Подальші дослідження молекулярних механізмів дії, а також доклінічні випробування із застосуванням тваринних моделей необхідні для оцінювання зазначених сполук як нових протиракових препаратів. Цель данного исследования состояла в анализе влияния антагонистов брадикинина на пролиферацию клеток глиобластомы человека U373. Методы. МТТ анализ пролиферации клеток. Результаты. BKM-570 продемонстрировал значительную антипролиферативную активность в клетках U373 (LC50 3,8 мкМ). Выводы. Антипролиферативные свойства антагонистов брадикинина показаны с использованием модели глиомы in vitro. Дальнейшие исследования молекулярных механизмов действия, а также доклинические испытания с применением животных моделей необходимы для оценки этих соединений в качестве новых противораковых препаратов. en Інститут молекулярної біології і генетики НАН України Вiopolymers and Cell Short Communications Growth suppression activity of bradykinin antagonists in glioma cells Антипроліферативна активність антагоністів брадикініну у клітинах гліоми Антипролиферативная активность антагонистов брадикинина в клетках глиомы Article published earlier |
| spellingShingle | Growth suppression activity of bradykinin antagonists in glioma cells Avdieiev, S.S. Gera, L. Hodges, R. Vassetzky, Y.S. Kavsan, V.M. Short Communications |
| title | Growth suppression activity of bradykinin antagonists in glioma cells |
| title_alt | Антипроліферативна активність антагоністів брадикініну у клітинах гліоми Антипролиферативная активность антагонистов брадикинина в клетках глиомы |
| title_full | Growth suppression activity of bradykinin antagonists in glioma cells |
| title_fullStr | Growth suppression activity of bradykinin antagonists in glioma cells |
| title_full_unstemmed | Growth suppression activity of bradykinin antagonists in glioma cells |
| title_short | Growth suppression activity of bradykinin antagonists in glioma cells |
| title_sort | growth suppression activity of bradykinin antagonists in glioma cells |
| topic | Short Communications |
| topic_facet | Short Communications |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/153733 |
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