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Индол-3-карбинол. Факты и только факты…

Вероятно, вы наслышаны и начитаны об индол-3-карбиноле (и3к) и имеете общее представление об этом замечательном веществе. Интернет просто кишит однообразными данными. Однако исследования, которые бы подтверждали его эффективность, найти достаточно сложно. Именно поэтому эту статью мы решили посвятить фактам об и3к, всевозможным исследованиям и обоснованным направлениям лечения и профилактики онкологии репродуктивной системы мужчин и женщин.

В рамках краткого предисловия скажем пару слов о стероидных половых гормонах, метаболиты которых и привлекли внимание мирового сообщества к индол-3-карбинолу. Ещё в далёких 70-х Генри Лемон, онколог и профессор университета штата Небраска, заявил, что гормон эстрадиол способен защитить от онкологической патологии. По его наблюдениям продолжительность жизни женщин с высоким уровнем эстрадиола после операции по удалению злокачественной опухоли молочной железы значительно выше. Исследования, которые проводились после заявления профессора, только подтверждают его наблюдения. Так, медики в Азии провели исследования, которые показали зависимость между уровнем эстрадиола и уровнем онкологической патологии. Результат показал, что в районах с высоким уровнем онкологии у людей зафиксирован низкий уровень эстрадиола. И наоборот, в районах, где уровень онкологии ниже среднего, уровень эстрадиола достаточно высокий. В дальнейшем проводилось множество исследований на животных, которые только подтверждали тот факт, что эстрадиол является онкопротектором. На следующем этапе стали задаваться вопросом, за счёт каких условий в некоторых районах у людей поддерживается достаточно высокий уровень эстрадиола. Оказалось, что в пищевой культуре этих районов основное место занимают овощи и главным образом семейства крестоцветных (в основном, это все виды капусты). К тому же, проводимые исследования показали, что метаболизм эстрадиола в этих районах также идет по «правильному» пути, минуя онкогенные (вызывающие онкологию) метаболиты. На рисунке ниже показаны превращения эстрадиола в организме. Как видно, онкогенным метаболитом является 16α-гидроксиэстрон, а «полезным» - 2-гидроксиэстрон:

 индол-3 карбинол

И3к является веществом, выделенным из овощей семейства крестоцветных и которое изучается уже на протяжении более 15 лет. Вначале считалось, что и3к способен влиять только на клетки, деление которых контролируется эстрогенами. Однако впоследствии выяснилось, что и3к вызывает гибель (апоптоз) онкоклеток независимо от наличия в них рецепторов к эстрогену. А это значит, что и3к обладает высоким избирательным противоопухолевым эффектом, влияющим на разные типы клеток, в том числе и клетки молочных желез.

Каким же образом на клеточном уровне и3к оказывает своё влияние?

Всё сводится к его антиэстрогенной активности. Самым наглядным примером эстрогенной стимуляции являются пролиферативные заболевания молочных желез, из которых самое грозное – рак. По данным ВООЗ, каждый год регистрируется более 550 тыс. новых случаев заболевания и в мире занимает второе место среди всей онкологии. Что же происходит в самой клетке? Эстроген является необходимым веществом как для здоровой, так и для опухолевой клетки. Эстроген взаимодействует с рецептором на клетке и образовавшийся комплекс попадает внутрь клетки. Дальше всё зависит от того, какая изоформа цитохромной системы Р-450 будет активирована:

  • 1-й вариант: через изоформу CYP1B1 (2,3). Эта форма образуется из самого эстрогена, в результате чего образуется метаболит 16α-гидроксиэстрон. Как уже говорилось ранее, этот метаболит обладает наиболее выраженной пролиферативной активностью по сравнению с нативным эстрогеном и его другими метаболитами, а, значит, обладает наибольшим онкогенным потенциалом;
  • 2-й вариант: через изоформу CYP1A1 (4,5). Эта изоформа превращает эстроген в 2-гидроксиэстрон. Этот метаболит, наоборот, выступает антагонистом эстрогеновых рецепторов и блокирует активацию рецепторов как эстрогеном, так и его другими метаболитами. Таким образом, прекращается синтез эстрогензависимых генов и клетка опухоли не может получать эстрогензависимую стимуляцию. В этом и заключается антиэстрогенная активность и3к.
  1. Lord R.S., Bongiovanni В., Bralley J.A. Estrogen metabolism and the diet-cancer connection, rationale for assessing the ratio of urinary hydroxylated estrogen metabolites. Altern Med Rev, 2002 Apr, 7(2), 112-29.
  1. Firestone G.L., Bjeldanes L.F. lndole-3-carbinol and З-З'-diindolylmethane antiproliferative signaling pathways control cell-cycle gene transcription in human breast cancer cells by regulating promoter-Sp1 transcription factor interactions. J Nutr, 2003, Jul, 133(7 Suppl), 2448S-2455S.
  2. Auborn K.J., Fan S., Rosen E.M., Goodwin L, Chandraskaren A., Williams D.E., Chen D., Carter Т.Н. lndole-3-carbinol is a negative regulator of estrogen. J Nutr, 2003, Jul, 133(7 Suppl), 2470S-2475S.
  3. Bradlow HI., Telang NT., Sepkovic D.W., Osborne M.P. 2-hydroxyestrone, the 'good' estrogen. J Endocrinol, 1996, Sep, 150 Suppl, S259-65.

Исходя из полученных данных в проведенных исследованиях, с 1995 года начали применять и3к как противоопухолевое средство для борьбы с раком молочной железы (5). Исследование показало, что уровень CYP1A1 регулировался в зависимости от концентрации и3к: ферментная активность CYP450 увеличивалась линейно от 10 до 150 | пмоль/мг белка при дозах от 1 до 500 ммоль и3к на одно животное. В сравнении с другими диетическими индолами, и3к проявлял наиболее сильную СУР1А1-стимулирующую активность, сопровождающуюся повышением 2-гидроксиэстрона. При этом наблюдалась статистически значимая регрессия эстрогензависимого роста опухолевой ткани по сравнению с таковой в контрольной группе животных.

Однако нужно заметить, что восприимчивость к и3к довольно непостоянна: индивидуальный ответ проявляется благодаря генетическим вариациям и зависит от индуцибельности CYP1A1. Этот эффект проанализирован в популяциях европейских и африкано-американских женщин: у первых соотношение 2/16а почти в 2 раза выше (2.25+1.42) (6).

  1. Taioli E., Garte S.J., Trachman J., Garbers S., Sepkovic D.W., Os-borne M.P., Mehl S., Bradlow H I . Ethnic differences in estrogen metabolism in healthy women. J Natl Cancer Inst, 1996, May 1, 88(9), 617.

 

Как упоминалось выше, антипролиферативная активность распространяется как на клетки, которые имеют эстрогеновые рецепторы, так и пролиферация (рост) которых происходит без участия эстрогенов (нет эстрогеновых рецепторов). Рост клеток без эстрогеновых рецепторов зависит от активности ростовых факторов (например, эпидермальный фактор роста, инсулино-подобный фактор роста и др.). Если нет никакого препятствиующего сигнала, то ростовые факторы активирую рецепторы и начинается синтез и выброс веществ для роста новых сосудов, белков и др. необходимых для опухолевой клетки факторов. И3к, попадая в клетку, блокирует большое количество таких сигнальных путей, что препятствует каскадной передаче пролиферативных сигналов (7, 8).

  1. Chinni S.R., Sarkar F.H. Akt inactivation is a key event in indole-3carbinol-induced apoptosis in PC-3 cells. Clin Cancer Res, 2002, Apr, 8(4), 1228-36.
  2. Brignall M.S. Prevention and treatment of cancer with indole-3-carbinol. Altern Med Rev, 2001, Dec, 6(6), 580-9.

Уже накоплены данные по подавлению индол-3-карбинолом опухолевых генов (9).

Гены

Функция в опухолевой клетке

Эффект и3к

Вах

Цитоплазматический белок, маркер апоптоза. Транслокация в митохондрию сопровождается выходом цитохрома с с последующим вовлечением каспаз 3 и 9 и развитием апоптоза

Усиление транскрипции

CDK6

Циклин-зависимая киназа. Стимулирует рост опухолевых клеток, наиболее активна в Gl-фазе клеточного цикла. Эстроген-независима

Блокада активности

Akt

Киназа, один из участников EGFиндуцируемого сигнального каскада. Стимулирует пролиферацию опухолевых клеток

Блокада активности, вызванная нарушением фосфорилирования

p27, р21, р16

CDK-ингибиторы, опухолевые супрессоры

Усиление транскрипции

HSP27

Белок теплового шока, выполняющий функцию стабилизации структуры белков, участвующих в пролиферации клеток. Экспрессия многократно повышена. Ингибитор апоптоза. Ассоциирован с агрессивной формой рака молочной железы. Вовлечен в метастазирование

Блокада активности

EGF, EGFR, TGFb, FGF

Ростовые факторы и их рецепторы. Стимулируют пролиферацию опухолей

Ингибирование транскрипции

NF-kB и NF-kB-индуцибельные гены

Ядерный фактор активации транскрипции генов, индуцируемых ростовыми факторами. Вовлечен в пролиферацию и выживание опухолевых клеток

Ингибирование транскрипции

  1. Lee I.J., Han F., Baek J., Hisatsune A., Kim K.C. Inhibition of MUC1 expression by indole-3-carbinol. Int J Cancer, 2004, May 10,109(6), 810-6.

Еще один механизм блокады опухолевого роста индол-3-карбинолом связан с ингибированием активности циклооксигеназы-2 (ЦОГ-2) - фермента, вовлеченного в синтез простагландинов (ПГE-2). ЦОГ-2 активируется в ответ на провоспалительные цитокины - фактор некроза опухоли-альфа (ФНО) и его "партнера" - интерлейкина-1 (ИЛ-1). Взаимодействие цитокинов со своими рецепторами приводит, в частности, к активации СЦОГ-2, синтезу ПГE2 с последующей транскрипцией фактора роста эндотелия сосудов (ФРЭС) - основного компонента опухолевого неоангиогенеза.

В итоге, и3к регулирует баланс про-и антиапоптотических факторов как на уровне транскрипции генов, так и посредством блокады активности зрелых белков. Сведения о влиянии и3к на регуляцию активности ключевых внутриклеточных пролиферативных сигналов суммированы в таблице:

Регуляция и3к транскрипции генов в опухолевой клетке

Гены

Функция в опухолевой клетке

Эффект и3к

CYP1A1

Гидроксилирование эстриола во 2 положении с образованием 2-гидроксиэстрона, - производного, обладающего антипролиферативной активностью

Усиление транскрипции через активацию Ah-peцептора

BRCA1

Специфический опухолевый супрессор в клетках молочной железы. Осуществляет блокаду транскрипции генов, индуцируемых ФНО

Усиление транскрипции

И3к обладает мощным антипролиферативным эффектом, который позволяет ингибировать воспаление, рост и пролиферацию опухолевых клеток, в том числе зараженных вирусом папилломатоза, а также рост новых сосудов. Кроме того, отмечен прямой апоптотический эффект и3к на опухолевые клетки: и3к усиливает экспрессию естественных опухолевых супрессоров, р21 и р53, которые, в свою очередь, являются ингибиторами циклин-зависимой киназы (CDK) - основного стимулятора опухолевого клеточного цикла (10, 11).

  1. Brandi G., Paiardini M., Cervasi В., Fiorucci C, Filippone P., De Marco C, Zaffaroni N.. Magnani M. A new indole-3-carbinol tetrameric derivative inhibits cyclin-dependent kinase 6 expression, and induces G1 cell cycle arrest in both estrogen-dependent and estrogen-independent breast cancer cell lines. Cancer Res, 2003, Jul 15, 63(14), 4028-36.
  2. Cram E.J., Liu B.D., Bjeldanes L.F., Firestone G.L. lndole-3-carbinol inhibits CDK6 expression in human MCF-7 breast cancer cells by disrupting Sp1 transcription factor interactions with a composite element in the CDK6 gene promoter. J Biol Chem, 2001, Jun, 22, 276(25), 22332-40.

Противовирусный потенциал и3к в отношении вируса папилломатоза человека

 Относительно недавно установлен еще один необычный эффект и3к: он вызывает апоптоз клеток, зараженных вирусом папилломатоза человека, в том числе теми типами вируса, которые обладают онкогенным потенциалом (12, 13). С учетом трудностей, сопровождающих терапию папилломатоза слизистых, данное свойство делает и3к незаменимым противовирусным препаратом с параллельной стимуляцией Т-клеточного звена иммунитета.

  1. Coll D.A., Rosen C.A., Auborn K" Potsic W.P., Bradlow H i . Treatment of recurrent respiratory papillomatosis with indole-3-carbinol. Am J Otolaryngol, 1997, Jul-Aug, 18(4), 283-5.
  2.  Stanley M. Chapter 17, Genital human papillomavirus infections-current and prospective therapies. J Natl Cancer Inst Monogr, 2003, 31,117-24.

Представленные данные неопровержимо доказывают преимущество индол-3-карбинола в терапии пролиферативных заболеваний молочной железы, к которым, вообще говоря, относится не только рак. Не меньшей проблемой перед маммологами стоит мастопатия. И если узелковую форму можно лечить хирургически, то диффузный вариант такому лечению не поддается. Поэтому и в этом случае объектом для терапии выбора может стать индол-3-карбинол.

Вместе с тем молекулярные механизмы, благодаря которым и3к вызывает избирательную гибель именно опухолевых клеток, еще мало изучены. Как видно из накопленных к настоящему времени данных, мы имеем лишь констатацию противоопухолевой активности и3к и пока не можем понять, как это вещество "отличает" опухолевые клетки от здоровых. Скорее всего, и3к лишь использует механизмы, которыми отличаются опухоли, постоянно живущие в условиях метаболического стресса. Эти механизмы направлены на регуляцию пролиферативной активности опухолевой клетки, ее выживание в условиях стресса, поддержание относительно постоянного гомеостаза. А это, в свою очередь, достигается усилением транскрипционного контроля белковых факторов, ответственных за эти процессы. Так, например, в клетках молочной железы повышена экспрессия ростовых факторов и их мембранно-связанных рецепторов (EGF, EGFR), факторов транскрипции (субъединиц NF-kB, SP-1, других активаторов транскрипции), ядерных рецепторов (в частности, рецепторов к эстрогенам), а также Ah-рецептора. И3к использует свой потенциал воздействия на сигнальные пути, индуцируемые указанными факторами, которых несравнимо больше в опухолевой, чем в здоровой клетке. Это, в свою очередь, приводит к кажущейся "избирательности" действия и3к, что на самом деле можно объяснить большей вероятностью взаимодействия. В пользу этого рассуждения говорит также тот факт, что потенциальными мишенями и3к являются, вообще говоря, все солидные опухоли, рост которых напрямую и не зависит от эстрогенов, и пролиферация которых проходит в эстрогеннезависимой манере (например, эстрогеннезависимые опухоли молочной железы, опухоли простаты). При этом никакой избирательности между разными типами опухолей и3к не проявляет. Просто там больше потенциальных объектов для взаимодействия. Другими словами, опухоль сама "предоставляет" множество объектов для проявления противоопухолевых активностей и3к.

Не менее интересным является свойство и3к предотвращать развитие опухолей, особенно когда речь идет о химически-индуцированном канцерогенезе. Вредное влияние окружающей среды вносит свой вклад в повышение риска мутагенности, нарушение метаболизма, сбоя защитных систем клетки, что немедленно сказывается на статистике смертей от опухолей в индустриально развитых странах. Мутагены, онкогены, циклические углеводороды, яды проникают в организм и накапливаются в тканях. Своеобразными "токсикологическими" воротами клетки служит Ah-рецептор, лигандами которого являются ариловые углеводороды. Долгое время не было известно ни одного природного лиганда для этого рецептора. Сейчас установлено, что один из них - индол-3-карбинол. Он служит селективным модулятором Ah-рецептора, изменяет его функции в плане регуляции экспрессии эстроген-зависимых генов и обладает сильным превентивным эффектом от активации Ah его химическими лигандами, такими, как, например, диоксин.

В заключении рекомендуем вам попробовать препарат Indole-3, который содержит 300 мг активного вещества индол-3-карбинол в одной капсуле

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