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

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ADDIN EN.CITE.DATA [58, 59] или в цитоплазме с помощью глутатионпероксидазы (GPx) (H2O2 + 2GSH 2H2O + GSSG). Причем, GPx катализирует реакцию не только с H2O2, но и с ROOH приводя к образованию спиртов (ROH) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWxsczwvQXV0aG9yPjxZZWFyPjE5NTc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA [60, 61].

Благодаря способности модулировать внутриклеточный уровень АФК антиоксиданты способны влиять на пролиферацию клеток. Как было отмечено выше (см. 1.1.1), в небольших количествах АФК индуцируют пролиферацию клеток. Снижение уровня Н2О2 за счет усиления экспрессии каталазы в эндотелиальных клетках и HER-2/Neu-трансформированных Rat-1 фибробластах приводило к ингибированию пролиферации этих клеток PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aYW5ldHRpPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48

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ADDIN EN.CITE.DATA [62, 63]. Понижение уровня АФК под действием синтетического антиоксиданта N-ацетил-цистеина (NAC) в клетках слизистой оболочки полости рта тажке приводило к замедлению пролиферативных процессов PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYXJnaTwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+PFJl

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ADDIN EN.CITE.DATA [64, 65].

Исследование пролиферации эмбриональных мышиных фибробластов с различным уровнем экспрессии MnСОД выявило, что пролиферация клеток содержащих MnСОД (+/+) замедляется по мере увеличения плотности популяции (контактное торможение).

Частичное подавление экспрессии MnСОД приводило к тому, что MnСОД (+/-) клетки были нечувствительны к контактному торможению и продолжали пролиферировать. Рост MnСОД (-/-) фибробластов был существенно замедлен. Усиление экспрессии MnСОД в MnСОД (+/-) клетках приводило к замедлению пролиферации. Ингибирование MnСОД в клетках экспрессирующих MnСОД (+/+), наоборот, приводило к усилению пролиферации. Интересно отметить, что обработка MnСОД (+/-) клеток с помощью Tiron, ловушки для O2-•, приводила к понижению уровня O2-• и замедлению пролиферации, указывая на важную роль O2-• в поддержании пролиферации. Замедление пролиферации также сопровождалось повышением концентрации Н2О2, продукта работы MnСОД ADDIN EN.CITE <EndNote><Cite><Author>Sarsour</Author><Year>2008</Year><RecNum>59</RecNum><DisplayText>[66]</DisplayText><record><rec-number>59</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">59</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sarsour, E. H.</author><author>Venkataraman, S.</author><author>Kalen, A. L.</author><author>Oberley, L. W.</author><author>Goswami, P. C.</author></authors></contributors><auth-address>Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA 52242, USA.</auth-address><titles><title>Manganese superoxide dismutase activity regulates transitions between quiescent and proliferative growth</title><secondary-title>Aging Cell</secondary-title><alt-title>Aging cell</alt-title></titles><periodical><full-title>Aging Cell</full-title><abbr-1>Aging cell</abbr-1></periodical><alt-periodical><full-title>Aging Cell</full-title><abbr-1>Aging cell</abbr-1></alt-periodical><pages>405-17</pages><volume>7</volume><number>3</number><edition>2008/03/12</edition><keywords><keyword>Cell Proliferation</keyword><keyword>Cells, Cultured</keyword><keyword>Cyclin B/metabolism</keyword><keyword>Cyclin B1</keyword><keyword>Cyclin D1/metabolism</keyword><keyword>Fibroblasts/cytology/metabolism</keyword><keyword>Humans</keyword><keyword>Hydrogen Peroxide/analysis</keyword><keyword>Reactive Oxygen Species/analysis/metabolism</keyword><keyword>Superoxide Dismutase/deficiency/ metabolism</keyword><keyword>Superoxides/analysis/metabolism</keyword></keywords><dates><year>2008</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1474-9726 (Electronic)&#xD;1474-9718 (Linking)</isbn><accession-num>18331617</accession-num><urls></urls><custom2>PMC2538945</custom2><custom6>Nihms59373</custom6><electronic-resource-num>10.1111/j.1474-9726.2008.00384.x</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[66]. Исследование посттрансляционных модификаций в молекуле MnСОД выявило различия в сайтах метилирования в пролиферирующих и покоящихся клетках. Уровень метилирования MnСОД в активно пролиферирующих клетках был ниже, чем в клетках, пролиферация которых была замедленна PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYXJzb3VyPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

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ADDIN EN.CITE.DATA [27].

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ADDIN EN.CITE.DATA [67-70]. В отличие от нормальных клеток, в которых уровень GSH снижался по мере увеличения количества клеток (т.н. контактное торможение), уровень GSH в опухолевых клеток был постоянно высоким PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdXR0ZXI8L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [71]. Вероятно, поэтому опухолевые клетки были невосприимчивы к действию NAC, предшественнику GSH. Обработка клеток карциномы молочной железы с помощью NAC не приводила к восстановлению редокс и формированию G1 блока PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZW5vbjwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJl

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ADDIN EN.CITE.DATA [72]. Снижение внутриклеточного уровня GSH за счет ингибирования -глутамилцистеинсинтетазы с помощью DL-бутионин-S,R-сульфоксимина (BSO), приводило к смещению внутриклеточного редокс-статуса в более окисленное состояние и аресту клеточной пролиферации PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZXVuZzwvQXV0aG9yPjxZZWFyPjE5OTM8L1llYXI+PFJl

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ADDIN EN.CITE.DATA [73].

Активность антиоксидантных ферментов в опухолевых клетках часто понижена по сравнению с нормальными клетками того же типа что, вероятно, является одной из причин активной пролиферации опухолевых клеток. Например, активность CuZnСОД и MnСОД в нормальных клетках печени мыши составляла, соответственно, 122 и 35 ед/мг, в то время как, в клетках гепатомы активность CuZnСОД падала до 40 ед/мг, а активность MnСОД вообще не определялась ADDIN EN.CITE <EndNote><Cite><Author>Oberley</Author><Year>1979</Year><RecNum>95</RecNum><DisplayText>[74]</DisplayText><record><rec-number>95</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">95</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Oberley, L. W.</author><author>Buettner, G. R.</author></authors></contributors><titles><title>Role of superoxide dismutase in cancer: a review</title><secondary-title>Cancer Res</secondary-title><alt-title>Cancer research</alt-title></titles><periodical><full-title>Cancer Res</full-title><abbr-1>Cancer research</abbr-1></periodical><alt-periodical><full-title>Cancer Res</full-title><abbr-1>Cancer research</abbr-1></alt-periodical><pages>1141-9</pages><volume>39</volume><number>4</number><edition>1979/04/01</edition><keywords><keyword>Animals</keyword><keyword>Cell Transformation, Neoplastic</keyword><keyword>Cells, Cultured</keyword><keyword>Humans</keyword><keyword>Hydrogen Peroxide/metabolism</keyword><keyword>Iron/metabolism</keyword><keyword>Manganese/metabolism</keyword><keyword>Models, Biological</keyword><keyword>Neoplasms/drug therapy/ metabolism</keyword><keyword>Oxidation-Reduction</keyword><keyword>Sulfhydryl Compounds/metabolism</keyword><keyword>Superoxide Dismutase/ deficiency</keyword><keyword>Superoxides/metabolism/therapeutic use</keyword></keywords><dates><year>1979</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0008-5472 (Print)&#xD;0008-5472 (Linking)</isbn><accession-num>217531</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[74]. Повышение экспрессии MnСОД в опухолевых клетках приводило к замедлению опухолевого роста PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PYmVybGV5PC9BdXRob3I+PFllYXI+MTk3OTwvWWVhcj48

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ADDIN EN.CITE.DATA [77, 78]

Резюмируя вышесказанное, важно отметить следующее: в клетке постоянно поддерживается баланс между про- и антиоксидантами. Наиболее распространенными прооксидантами являются АФК, к которым относятся: О2•-, Н2О2, НО•, ROO• и др. Основные регуляторы уровня внутриклеточных прооксидантов – антиоксиданты MnСОД, каталаза и GSH. Повышение уровня АФК приводит к гибели клетки, однако в небольших количествах АФК способны индуцировать пролиферативные процессы. Быстро делящиеся опухолевые клетки часто характеризуются повышенным уровнем АФК и пониженной активностью антиоксидантной системы, что возможно является одной из причин их активной пролиферации. Повышение антиоксидантной активности и понижение уровня АФК приводят к замедлению пролиферативных процессов, это открывает возможность контролировать пролиферацию опухолевых с помощью антиоксидантов.

РАЗДЕЛ 1.2.

Редокс-регуляция клеточной пролиферацииДля того чтобы понять, механизм редокс-регуляции пролиферации, необходимо вспомнить - что такое пролиферация. Пролиферация - это процесс увеличения количества клеток, определяющийся соотношением скоростей деления клеток и их гибели. Гибель клеток может происходить как в результате повреждения целостности клетки (некроз), так и путем активации внутриклеточных программ (апоптоз). Деление клетки строго регулируется как внутренними программами, так и внешними факторами (факторы роста, цитокины и др.), воздействующими на внутренние программы. Каждому делению предшествует комплекс последовательных внутриклеточных изменений, т.н. клеточный цикл, основная цель которого – удвоение содержимого клетки и его равномерное распределение между двумя дочерними клетками при делении.

1.2.1. Клеточный цикл и его регуляцияКлеточный цикл представляет собой высокоорганизованную и строго регулируемую последовательность переходов от G1 фазы к S, к G2 и митозу (М). Переход от одной фазы к другой регулируется последовательной экспрессией белков циклинов и активацией циклин-зависимых киназ (cyclin dependent kinase, CDK). CDK представляют собой серин/треоининовые протеинкиназы, которые активируются при соединении с циклинами и запускают события клеточного цикла, путем фосфорилирования соответствующих остатков в белках-мишенях ADDIN EN.CITE <EndNote><Cite><Author>Evans</Author><Year>1983</Year><RecNum>466</RecNum><DisplayText>[79]</DisplayText><record><rec-number>466</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">466</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Evans, T.</author><author>Rosenthal, E. T.</author><author>Youngblom, J.</author><author>Distel, D.</author><author>Hunt, T.</author></authors></contributors><titles><title>Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division</title><secondary-title>Cell</secondary-title><alt-title>Cell</alt-title></titles><periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></periodical><alt-periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></alt-periodical><pages>389-96</pages><volume>33</volume><number>2</number><edition>1983/06/01</edition><keywords><keyword>Alkaloids/pharmacology</keyword><keyword>Ammonia/pharmacology</keyword><keyword>Animals</keyword><keyword>Cell Division</keyword><keyword>Colchicine/pharmacology</keyword><keyword>Cytochalasins/metabolism</keyword><keyword>Egg Proteins/analysis/ physiology</keyword><keyword>Female</keyword><keyword>Methionine/metabolism</keyword><keyword>Ovum/metabolism</keyword><keyword>Paclitaxel</keyword><keyword>RNA, Messenger/ metabolism</keyword><keyword>Sea Urchins</keyword><keyword>Zygote/ metabolism</keyword></keywords><dates><year>1983</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0092-8674 (Print)&#xD;0092-8674 (Linking)</isbn><accession-num>6134587</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[79]. На Рис. 1.1. представлены основные циклин/CDK комплексы позвоночных, специфичные для той или иной фазы клеточного цикла. Уровень циклинов меняется по мере прогрессии клеточного цикла, приводя к колебаниям активности CDK (См. Рис. 1.1). Помимо циклинов активность CDK комплексов регулируется с помощью CDK-активирующей киназы (CDK-activating kinase, CAK), ингибиторов CDK (cyclin-dependent kinase inhibitor protein, CKI), а также протеолитическими процессами (убиквитинирование) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGJlcnRzPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48

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ADDIN EN.CITE.DATA [80, 81]. Для полной активации комплекса циклин/CDK необходимо фосфорилирование CDK по Thr161 (CDK1), Thr160 (CDK2) или Thr172/177 (CDK4/6), которое осуществляется в ядре с помощью CAK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdWNvbW11bjwvQXV0aG9yPjxZZWFyPjE5OTE8L1llYXI+

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ADDIN EN.CITE.DATA [83-85]. САК состоит из трех субъединиц: CDK7, циклин H и белка Mat1, который активирует комплекс циклин H/CDK7. Связывание с циклином приводит к конформационным изменениям в CDK, которые делают возможным фосфорилирование CDK с помощью CAK ADDIN EN.CITE <EndNote><Cite><Author>Porter</Author><Year>2003</Year><RecNum>471</RecNum><DisplayText>[86]</DisplayText><record><rec-number>471</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">471</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Porter, L. A.</author><author>Donoghue, D. J.</author></authors></contributors><auth-address>Department of Chemistry &amp; Biochemistry, University of California, San Diego, La Jolla, CA 92093-0367, USA.</auth-address><titles><title>Cyclin B1 and CDK1: nuclear localization and upstream regulators</title><secondary-title>Prog Cell Cycle Res</secondary-title><alt-title>Progress in cell cycle research</alt-title></titles><periodical><full-title>Prog Cell Cycle Res</full-title><abbr-1>Progress in cell cycle research</abbr-1></periodical><alt-periodical><full-title>Prog Cell Cycle Res</full-title><abbr-1>Progress in cell cycle research</abbr-1></alt-periodical><pages>335-47</pages><volume>5</volume><edition>2003/11/05</edition><keywords><keyword>Active Transport, Cell Nucleus/drug effects/genetics</keyword><keyword>Animals</keyword><keyword>Antineoplastic Agents/pharmacology</keyword><keyword>CDC2 Protein Kinase/drug effects/ genetics/metabolism</keyword><keyword>Cell Cycle/drug effects/ physiology</keyword><keyword>Cell Nucleus/drug effects/ metabolism</keyword><keyword>Cyclin B/drug effects/ genetics/metabolism</keyword><keyword>Cyclin B1</keyword><keyword>Drug Evaluation, Preclinical</keyword><keyword>Humans</keyword><keyword>Phosphorylation/drug effects</keyword></keywords><dates><year>2003</year></dates><isbn>1087-2957 (Print)&#xD;1087-2957 (Linking)</isbn><accession-num>14593728</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[86]. Активность CAK-киназы постоянна на протяжении всего клеточного цикла ADDIN EN.CITE <EndNote><Cite><Author>Lolli</Author><Year>2005</Year><RecNum>465</RecNum><DisplayText>[87]</DisplayText><record><rec-number>465</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">465</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lolli, G.</author><author>Johnson, L. N.</author></authors></contributors><auth-address>Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, Oxford, UK. graziano@biop.ox.ac.uk</auth-address><titles><title>CAK-Cyclin-dependent Activating Kinase: a key kinase in cell cycle control and a target for drugs?</title><secondary-title>Cell Cycle</secondary-title><alt-title>Cell cycle (Georgetown, Tex.)</alt-title></titles><periodical><full-title>Cell Cycle</full-title><abbr-1>Cell cycle (Georgetown, Tex.)</abbr-1></periodical><alt-periodical><full-title>Cell Cycle</full-title><abbr-1>Cell cycle (Georgetown, Tex.)</abbr-1></alt-periodical><pages>572-7</pages><volume>4</volume><number>4</number><edition>2005/05/07</edition><keywords><keyword>Animals</keyword><keyword>Antineoplastic Agents/pharmacology</keyword><keyword>Cell Cycle</keyword><keyword>Cyclin-Dependent Kinases/metabolism/ physiology</keyword><keyword>Gene Expression Regulation</keyword><keyword>Humans</keyword><keyword>Models, Biological</keyword><keyword>Models, Molecular</keyword><keyword>Neoplasms/ therapy</keyword><keyword>Receptor Protein-Tyrosine Kinases/ physiology</keyword></keywords><dates><year>2005</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1551-4005 (Electronic)&#xD;1551-4005 (Linking)</isbn><accession-num>15876871</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[87].

lefttopРисунок 1.1. Основные фазо-специфические комплексы циклинов с циклин-зависимыми киназами у позвоночных. Из ADDIN EN.CITE <EndNote><Cite><Author>Coller</Author><Year>2007</Year><RecNum>170</RecNum><DisplayText>[82]</DisplayText><record><rec-number>170</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">170</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Coller, H. A.</author></authors></contributors><auth-address>Department of Molecular Biology, Lewis Thomas Laboratory, Room 140, Princeton University, Princeton, New Jersey 08544-1014, USA. hcoller@princeton.edu</auth-address><titles><title>What&apos;s taking so long? S-phase entry from quiescence versus proliferation</title><secondary-title>Nat Rev Mol Cell Biol</secondary-title><alt-title>Nature reviews. Molecular cell biology</alt-title></titles><periodical><full-title>Nat Rev Mol Cell Biol</full-title><abbr-1>Nature reviews. Molecular cell biology</abbr-1></periodical><alt-periodical><full-title>Nat Rev Mol Cell Biol</full-title><abbr-1>Nature reviews. Molecular cell biology</abbr-1></alt-periodical><pages>667-70</pages><volume>8</volume><number>8</number><edition>2007/07/20</edition><keywords><keyword>Animals</keyword><keyword>DNA Replication/ physiology</keyword><keyword>G1 Phase/ physiology</keyword><keyword>Humans</keyword><keyword>S Phase/ physiology</keyword><keyword>Time Factors</keyword></keywords><dates><year>2007</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1471-0072 (Print)&#xD;1471-0072 (Linking)</isbn><accession-num>17637736</accession-num><urls></urls><electronic-resource-num>10.1038/nrm2223</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[82], с изменениями. См. пояснения в тексте.

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