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«Антипролиферативное действие карнозина и его производных на опухолевые клетки нейрального происхождения ...»

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Увеличение количества G2 клеток сопровождалось усилением экспрессии циклина В1. Циклин В1 представляет собой функциональную субъединицу комплекса циклин В1/CDK1, который регулирует прогрессию клетки через G2 фазу (Рис. 3.2.8) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LcmVrPC9BdXRob3I+PFllYXI+MTk5MTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA [131]. Экспрессия циклина В1 усиливается в поздней S-фазе, достигает максимума в G2, и резко снижается в середине митоза. В G1-фазе циклин В1 не детектируется ADDIN EN.CITE <EndNote><Cite><Author>Grana</Author><Year>1995</Year><RecNum>259</RecNum><DisplayText>[81]</DisplayText><record><rec-number>259</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">259</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Grana, X.</author><author>Reddy, E. P.</author></authors></contributors><auth-address>Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.</auth-address><titles><title>Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs)</title><secondary-title>Oncogene</secondary-title><alt-title>Oncogene</alt-title></titles><periodical><full-title>Oncogene</full-title><abbr-1>Oncogene</abbr-1></periodical><alt-periodical><full-title>Oncogene</full-title><abbr-1>Oncogene</abbr-1></alt-periodical><pages>211-9</pages><volume>11</volume><number>2</number><edition>1995/07/20</edition><keywords><keyword>Animals</keyword><keyword>Cell Cycle/ physiology</keyword><keyword>Cyclin-Dependent Kinases/ antagonists &amp; inhibitors/ physiology</keyword><keyword>Cyclins/ physiology</keyword><keyword>Enzyme Inhibitors/ pharmacology</keyword><keyword>Genes, Tumor Suppressor</keyword><keyword>Humans</keyword></keywords><dates><year>1995</year><pub-dates><date>Jul 20</date></pub-dates></dates><isbn>0950-9232 (Print)&#xD;0950-9232 (Linking)</isbn><accession-num>7624138</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[81]. Таким образом, увеличение уровня циклина В1 в пробах обработанных карнозином может быть следствием повышенного содержания клеток в G2-фазе. С другой стороны, карнозин может напрямую активировать экспрессию циклина В1 независимо от индукции G2-блока. Дополнительные исследования необходимы для изучения механизма активации экспрессии циклина В1 в ответ на действие карнозина.

Мы полагаем, что индукция G2 блока под действием карнозина может быть также опосредована через фосфатазу Cdc25C, которая является редокс-чувствительным ферментом и играет важную роль в регуляции работы комплекса циклин В1/CDK1 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZW5nPC9BdXRob3I+PFllYXI+MTk5NzwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA [138, 177]. Thomas et al. показали, что низкомолекулярный антиоксидант витамин С индуцирует G2 блок в клетках HeLa и T98G. При более подробном исследовании механизма данного явления было выявлено, что витамин С препятствует перемещению Cdc25C в ядро, а следовательно и активации комплекса циклин В1/CDK1 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaG9tYXM8L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [181]. В результате, несмотря на наличие комплекса циклин В1/CDK1 в клетке прогрессии клеточного цикла не происходило. Нами также было замечено, что рост уровня циклина В1 начинался одновременно с ростом уровня белка MnСОД, подтверждая наше предположение о том, что увеличение активности MnСОД приводит к изменениям в прогрессии клеточного цикла и формированию G2 блока. Исходя из наших данных, сопоставленных с данными литературы, был сделан вывод о том, что индуцированные карнозином изменения в соотношении внутриклеточных про- и антиоксидантов индуцирует G2 блок и увеличивают уровень циклина В1.

У карнозина существует несколько природных производных, среди них: ацетил-карнозин (N-ацетил--аланил-L-гистидин), анзерин (-аланил-3-метил-L-гистидин), гомокарнозин (у-амино-бутирил-L-гистидин). Изучение структурно-функциональных особенностей карнозина и его производных в отношении подавления пролиферации опухолевых клеток может помочь оценить степень вовлеченности отдельных частей молекулы в исследуемый эффект карнозина. Исследование антипролиферативых свойств производных карнозина выявило, что все исследованные производные карнозина ингибировали пролиферацию опухолевых клеток. Эффективность действия исследованных дипептидов возрастала в следующем порядке: ацетил-карнозин < карнозин гомокарнозин < анзерин (Рис. 3.1.4.А, 3.3.1, 3.3.2, 3.3.3). Анализ распределения клеток по фазам клеточного цикла в контроле и пробах обработанных дипептидами показал, что все исследованные вещества индуцируют накопление клеток в G2 фазе клеточного цикла. Клетки U-118-MG обработанные анзерином также демонстрирововали небольшое увеличение количества клеток в G1 фазе, что, возможно, было причиной более сильного антипролиферативного эффекта анзерина. Исходя из полученных данных, был сделан вывод о том, что ацетилирование карнозина снижает его антипролиферативные способности, в то время как метилирование, наоборот, усиливает антипролиферативный эффект.

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ADDIN EN.CITE.DATA [15, 264]. Совпадение принципов изменения силы антиоксидантного и антипролиферативного эффектов еще раз указывает на сопряженность между антиоксидантным и антипролиферативным свойствами карнозина.

Синтетический аналог карнозина - L-гистидин--аланин, представляющий собой т.н. «карнозина наоборот» также индуцировал накопление клеток в G2 фазе клеточного цикла и ингибировал пролиферацию опухолевых клеток (Рис. 3.1.4.Б). Причем, диапазон эффективных концентраций для антипролиферативного эффекта L-гистидин--аланина был в 10 раз ниже (5 – 10 мМ), чем для карнозина (50 - 100 мМ). Однако, при концентрации выше 10 мМ L-гистидин--аланин приводил к интенсивной гибели опухолевых клеток. Токсичность «карнозина наоборот» может быть связана с положением L-гистидина на первом месте. Известно, что в концентрации выше 5 мМ гистидин обладает цитотоксическими действием. Добавление -аланина к молекуле гистидина в молекуле карнозина, вероятно, способствует снижению токсичности гистидина. Было показано, что токсичность гистидина связана с присутствием ионов железа, удаление ионов железа из среды снижало токсический эффект гистидина. Имидазольное кольцо в молекуле гистидина способно хелатировать железо, отдавая протон от азота 1N. Металлы в металлоферментах часто координируются с помощью гистидина через незащищенный азот в имидазоле. Предполагается, что гистидин способен отнимать т.н. «хелатируемое железо», железо слабосвязанное с внутриклеточными ферментами, и делать его более доступным для окисления под действием АФК PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYXVlbjwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJl

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ZE5vdGU+AG==

ADDIN EN.CITE.DATA [265, 266]. Перемещение L-гистидина на первое место в молекуле «карнозина наоборот» делает имидазольное кольцо более открытым, и, следовательно, более доступным для взаимодействий, что, вероятно, является причиной цитотоксичности высоких концентраций L-гистидин--аланина.

Инкубация с синтетическим трипептидом пинеалоном приводила к снижению внутриклеточного уровня АФК в клетках РС-12 по сравнению с необработанным контролем (Рис. 3.1.5.А). Наши результаты согласовывались с полученными ранее данными об антиоксидантных свойствах пинеалона, продемонстрированных на модели гиперборической гипоксии PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb3ppbmE8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [244-246]. Кроме того, на клетках РС-12 мы показали, что пинеалон обладает защитным антиоксидантным действием. Пинеалон частично препятствовал росту внутрикелточного уровня АФК индуцированного действием Н2О2 и снижал уровень клеточной гибели (Рис. 3.1.5). Анализ клеточного цикла выявил, что подобно карнозину, инкубация с пинеалоном приводит к увеличению количества S и G2/М клеток по сравнению с контролем (Рис. 3.1.6). Однако, для достижения сходного эффекта пинеалон требовался в концентрациях на несколько порядков ниже, чем карнозин (нМ – для пинеалона, мМ – для карнозина). Ранее в нашей лаборатории было показано, что пинеалон препятствует росту ERK1/2 в гранулярных клетках мозжечка индуцированное действием уабаина ADDIN EN.CITE <EndNote><Cite><Author>Rybakova</Author><Year>2012</Year><RecNum>345</RecNum><DisplayText>[234]</DisplayText><record><rec-number>345</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">345</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rybakova, Y.</author><author>Akkuratov, E.</author><author>Kulebyakin, K.</author><author>Brodskaya, O.</author><author>Dizhevskaya, A.</author><author>Boldyrev, A.</author></authors></contributors><auth-address>International Biotechnological Center of MV Lomonosov Moscow State University, Moscow, Russia. julie_ribakova@yahoo.com</auth-address><titles><title>Receptor-mediated oxidative stress in murine cerebellar neurons is accompanied by phosphorylation of MAP (ERK 1/2) kinase</title><secondary-title>Curr Aging Sci</secondary-title><alt-title>Current aging science</alt-title></titles><periodical><full-title>Curr Aging Sci</full-title><abbr-1>Current aging science</abbr-1></periodical><alt-periodical><full-title>Curr Aging Sci</full-title><abbr-1>Current aging science</abbr-1></alt-periodical><pages>225-30</pages><volume>5</volume><number>3</number><edition>2013/02/08</edition><dates><year>2012</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1874-6128 (Electronic)</isbn><accession-num>23387889</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[234]. Поскольку активация ERK1/2 необходима для прогрессии клеточного цикла, снижение активности ERK1/2 под действием пинеалона может быть одним из механизмов индукции G2 блока в его присутствии. Кроме того, аминокислотный состав пинеалона и карнозина различается, указывая на то, что действие исследуемых короткоцепочечных пептидов на клеточный цикл, видимо, обосновано не присутствием конкретной аминокислоты, а скорее всего антиоксидантными свойствами веществ. Глиобластома – это наиболее частая и агрессивная форма опухоли головного мозга ADDIN EN.CITE <EndNote><Cite><Author>Louis</Author><Year>2007</Year><RecNum>378</RecNum><DisplayText>[269]</DisplayText><record><rec-number>378</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">378</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Louis, D. N.</author><author>Ohgaki, H.</author><author>Wiestler, O. D.</author><author>Cavenee, W. K.</author><author>Burger, P. C.</author><author>Jouvet, A.</author><author>Scheithauer, B. W.</author><author>Kleihues, P.</author></authors></contributors><auth-address>Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.</auth-address><titles><title>The 2007 WHO classification of tumours of the central nervous system</title><secondary-title>Acta Neuropathol</secondary-title><alt-title>Acta neuropathologica</alt-title></titles><periodical><full-title>Acta Neuropathol</full-title><abbr-1>Acta neuropathologica</abbr-1></periodical><alt-periodical><full-title>Acta Neuropathol</full-title><abbr-1>Acta neuropathologica</abbr-1></alt-periodical><pages>97-109</pages><volume>114</volume><number>2</number><edition>2007/07/10</edition><keywords><keyword>Central Nervous System Neoplasms/ classification</keyword><keyword>Humans</keyword><keyword>World Health Organization</keyword></keywords><dates><year>2007</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0001-6322 (Print)&#xD;0001-6322 (Linking)</isbn><accession-num>17618441</accession-num><urls></urls><custom2>PMC1929165</custom2><electronic-resource-num>10.1007/s00401-007-0243-4</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[269]. На сегодняшний день лечение глиобластомы носит скорее паллиативный характер и продлевает жизнь больного максимум на 2 года ADDIN EN.CITE <EndNote><Cite><Author>Kesari</Author><Year>2011</Year><RecNum>409</RecNum><DisplayText>[270]</DisplayText><record><rec-number>409</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">409</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kesari, S.</author></authors></contributors><auth-address>Department of Neurosciences, Moores Cancer Center, UC San Diego Health System, La Jolla, CA 92093-0819, USA. skesari@ucsd.edu</auth-address><titles><title>Understanding glioblastoma tumor biology: the potential to improve current diagnosis and treatments</title><secondary-title>Semin Oncol</secondary-title><alt-title>Seminars in oncology</alt-title></titles><periodical><full-title>Semin Oncol</full-title><abbr-1>Seminars in oncology</abbr-1></periodical><alt-periodical><full-title>Semin Oncol</full-title><abbr-1>Seminars in oncology</abbr-1></alt-periodical><pages>S2-10</pages><volume>38 Suppl 4</volume><edition>2011/12/07</edition><keywords><keyword>Brain Neoplasms/genetics/ pathology/ therapy</keyword><keyword>Glioblastoma/genetics/ pathology/ therapy</keyword><keyword>Humans</keyword><keyword>Practice Guidelines as Topic</keyword><keyword>Prognosis</keyword></keywords><dates><year>2011</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1532-8708 (Electronic)&#xD;0093-7754 (Linking)</isbn><accession-num>22078644</accession-num><urls></urls><electronic-resource-num>10.1053/j.seminoncol.2011.09.005</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[270]. Одним из наиболее эффективных способов лечения глиобластомы является лучевая терапия, применение которой ограничено повреждающим действием на нормальные ткани. Соединения, способные усиливать гибель опухолевых клеток, предохраняя при этом нормальные ткани, представляют собой одно из наиболее актуальных направлений исследований.

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ADDIN EN.CITE.DATA [218-220]. Кроме того, карнозин снижал степень повреждения плазмиды ДНК и количество разрывов в цепи ДНК, индуцированные действием ионизирующего излучения ADDIN EN.CITE <EndNote><Cite><Author>Fu</Author><Year>2009</Year><RecNum>508</RecNum><DisplayText>[271]</DisplayText><record><rec-number>508</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">508</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fu, Haiying</author><author>Katsumura, Yosuke</author><author>Lin, Mingzhang</author><author>Muroya, Yusa</author><author>Hata, Kuniki</author><author>Fujii, Kentaro</author><author>Yokoya, Akinari</author><author>Hatano, Yoshihiko</author></authors></contributors><titles><title>Free radical scavenging and radioprotective effects of carnosine and anserine</title><secondary-title>Radiation Physics and Chemistry</secondary-title></titles><periodical><full-title>Radiation Physics and Chemistry</full-title></periodical><pages>1192-1197</pages><volume>78</volume><number>12</number><keywords><keyword>Free radicals</keyword><keyword>Carnosine</keyword><keyword>Anserine</keyword><keyword>Scavenging activity</keyword><keyword>DNA</keyword></keywords><dates><year>2009</year><pub-dates><date>12//</date></pub-dates></dates><isbn>0969-806X</isbn><urls><related-urls><url>http://www.sciencedirect.com/science/article/pii/S0969806X09003508</url></related-urls></urls><electronic-resource-num>http://dx.doi.org/10.1016/j.radphyschem.2009.07.023</electronic-resource-num></record></Cite></EndNote>[271]. Исходя из полученных нами данных мы предполагаем, что карнозин способен избирательно снижать выживаемость опухолевых клеток под действием ионизирующего излучения, защищая при этом нормальные клетки. Полученные нами данные могут быть использованы на практике для разработки протоколов применения карнозина в терапии опухолей головного мозга.

ВЫВОДЫ1. Исследован характер воздействия карнозина на пролиферацию культур опухолевых клеток: феохромоцитомы крысы (РС-12), карциномы горла и рта (FaDu и Cal27), карциномы молочной железы (MB231) и глиобластомы человека (U-118-MG).

Обнаружено, что карнозин ингибирует пролиферацию всех исследованных клеточных линий. Наиболее выраженный эффект проявлялся на клетках глиобластомы человека U-118-MG;

2. Изучено влияние карнозина на уровень АФК и активность антиоксидантных ферментов глиобластомы. Выявлено, что ингибирование пролиферации клеток глиобластомы под действием карнозина сопровождается снижением уровня АФК и увеличением активности MnСОД;

3. Исследовано воздействие карнозина на клеточный цикл клеток РС-12 и U-118-MG. Установлено, что изменения в антиоксидантной системе сопровождаются накоплением клеток в G2 фазе клеточного цикла и усилением экспрессии циклина В1;

4. Проведено сравнение антипролиферативного эффекта карнозина с действием его производных и синтетического трипептида пинеалона. Выявлено, что метилированное производное карнозина, анзерин, ингибирует пролиферацию клеток опухолевых клеток эффективнее, чем карнозин;

5. Исследован эффект совместного применения карнозина и ионизирующего излучения на гибель опухолевых клеток. Обнаружено, что предварительная инкубация клеток с карнозином снижает выживаемость клеток глиобластомы под действием ионизирующего излучения.

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