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Химиопрофилактические свойства 3,3'-дииндолилметана: от экспериментального до клинического применения
Власов А.В., Якушевская О.В. Химиопрофилактические свойства 3,3'-дииндолилметана: от экспериментального до клинического применения. Гинекология. 2024;26(3):270–274.
DOI: 10.26442/20795696.2024.3.202953
© ООО «КОНСИЛИУМ МЕДИКУМ», 2024 г.
DOI: 10.26442/20795696.2024.3.202953
© ООО «КОНСИЛИУМ МЕДИКУМ», 2024 г.
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Vlasov AV, Yakushevskaya OV. Chemopreventive properties of 3,3'-diindolylmethane: From experimental to clinical studies. A review. Gynecology. 2024;26(3):270–274. DOI: 10.26442/20795696.2024.3.202953
Материалы доступны только для специалистов сферы здравоохранения. Авторизуйтесь или зарегистрируйтесь.
Аннотация
В основе идеи канцеропротективного направления в медицине лежит коррекция инициальных эпигенетических нарушений в клетке, т.е. реализация реверсии патологического генома. Накоплены убедительные данные, подтверждающие потенциальную противоопухолевую активность соединений, полученных из овощей семейства крестоцветных рода Brassicaceae. Индол-3-карбинол и 3,3'-дииндолилметан (DIM) исследовали на предмет их использования в качестве химиопрофилактических средств. DIM образуется в кислой среде желудка в результате димеризации мономеров индол-3-карбинола. В настоящее время невозможно выделить специфический вектор влияния DIM на молекулярном уровне. В обзоре суммированы плейотропные эффекты DIM, направленные на коррекцию обратимых эпигенетических изменений в опухолевых клетках. Сделан акцент на наиболее важные клеточные и молекулярные события, которые эффективно модулируются DIM. Основной профиль компетенций DIM касается управления передачей внутриклеточных сигналов и коррекции начальных молекулярно-генетических изменений на уровне ключевых участников сигнальных путей (NF-κB/Wnt/Akt/mTOR), приводящих к развитию онкологического заболевания. Способность DIM дифференцированно модулировать апоптоз опухолевых клеток наблюдали в доклинических исследованиях. Сформулировано предположение о том, что с помощью DIM возможно увеличить эффективность химиотерапевтических соединений с разными молекулярными мишенями, т.е. повысить химиосенсибилизацию. DIM перешел в фазу III клинических испытаний, предварительные результаты которых подтверждают его перспективность как в качестве самостоятельной терапии, так и в сочетании с другими компонентами противоопухолевого лечения. Установление диапазона эпигенетического контроля DIM молекулярных и генетических изменений при различных онкологических заболеваниях позволит оптимизировать подходы терапевтической эпигенетики.
Ключевые слова: 3,3'-дииндолилметан, индол-3-карбинол, крестоцветные рода Brassicaceae, химиопрофилактика, канцерогенез, эпигенетические изменения
Ключевые слова: 3,3'-дииндолилметан, индол-3-карбинол, крестоцветные рода Brassicaceae, химиопрофилактика, канцерогенез, эпигенетические изменения
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The basis for the prevention of cancer is the correction of initial epigenetic disorders in the cell, i.e. implementation of pathological genome reversion. Convincing evidence has accumulated to support the potential antitumor activity of compounds derived from cruciferous vegetables of the genus Brassicaceae. Indole-3-carbinol and 3,3'-diindolylmethane (DIM) have been investigated for their use as chemopreventive agents. DIM is formed in the acidic environment of the stomach as a result of dimerization of indole-3-carbinol monomers. Currently, it is impossible to identify a specific vector of influence of DIM at the molecular level. In this review, we summarize the pleiotropic effects of DIM aimed at correcting reversible epigenetic changes in tumor cells. Emphasis will be placed on the major cellular and molecular events that are effectively modulated by DIM. The main profile of DIM competencies concerns the management of intracellular signal transmission and correction of initial molecular genetic changes at the level of key participants in signaling pathways (NF-κB/Wnt/Akt/mTOR) leading to the development of cancer. The ability of DIM to differentially modulate tumor cell apoptosis has been observed in preclinical studies. It has been suggested that using DIM it is possible to increase the effectiveness of chemotherapeutic compounds with different molecular targets, thereby increasing chemosensitization. DIM has entered phase III clinical trials, with preliminary results confirming its promise both as a stand-alone drug and in combination with other components of anticancer therapy. Establishing the range of epigenetic control of DIM molecular and genetic changes in various cancers will allow optimization of therapeutic epigenetics approaches.
Keywords: 3,3'-diindolylmethane, indole-3-carbinol, Brassicaceae, chemoprevention, carcinogenesis, epigenetic changes
Полный текст
Список литературы
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10. Heath EI, Heilbrun LK, Li J, et al. A phase I dose-escalation study of oral BR-DIM (BioResponse 3,3'-diindolylmethane) in castrate-resistant, non-metastatic prostate cancer. Am J Transl Res. 2010;2(4):402-11.
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DOI:10.1210/en.2009-1028
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DOI:10.1016/B978-0-12-812494-9.00005-6
18. Li Y, Li X, Guo B. Chemopreventive agent 3,3’-diindolylmethane selectively induces proteasomal degradation of class I histone deacetylases. Cancer Res. 2010;70(2):646-54. DOI:10.1158/0008-5472.CAN-09-1924
19. Li XJ, Park ES, Park MH, Kim SM. 3,3’-Diindolylmethane suppresses the growth of gastric cancer cells via activation of the Hippo signaling pathway. Oncol Rep. 2013;30(5):2419-26. DOI:10.3892/or.2013.2717
20. Biersack B. 3,3’-Diindolylmethane and its derivatives: nature-inspired strategies tackling drug resistant tumors by regulation of signal transduction, transcription factors and microRNAs. Cancer Drug Resist. 2020;3(4):867-78. DOI:10.20517/cdr.2020.53
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22. Xu J, Qi G, Wang W, Sun XS. Advances in 3D peptide hydrogel models in cancer research. NPJ Sci Food. 2021;5(1):14. DOI:10.1038/s41538-021-00096-1
23. Elackattu AP, Feng L, Wang Z. A controlled safety study of diindolylmethane in the immature rat model. Laryngoscope. 2009;119(9):1803-8. DOI:10.1002/lary.20526
24. National Toxicology Program. Toxicology studies of indole-3-carbinol in F344/N rats and B6C3F1/N mice and toxicology and carcinogenesis studies of indole-3-carbinol in Harlan Sprague Dawley rats and B6C3F1/N mice (gavage studies). Natl Toxicol Program Tech Rep Ser. 2017;(584). DOI:10.22427/NTP-TR-584
25. European Commission. EU Novel food catalogue. Available at: https://webgate.ec.europa.eu/fip/novel_food_catalogue. Accessed: 16.07.2024.
2. Якушевская О.В., Юрова М.В. Модуляция эпигенетических изменений и химиопрофилактика: 3,3’-дииндолилметан. Женское здоровье и репродукция. 2023;6(61):35-47 [Yakushevskaya OV, Iurova MV. Modulation of epigenetic changes and chemoprophylaxis: 3,3’-diindolylmathane. Women’s Health and Reproduction. 2023;6(61):35-47 (in Russian)]. DOI:10.31550/2712-85982023-6-4-ZhZiR
3. Reyes-Hernández OD, Figueroa-González G, Quintas-Granados LI, et al. 3,3’-Diindolylmethane and indole-3-carbinol: potential therapeutic molecules for cancer chemoprevention and treatment via regulating cellular signaling pathways. Cancer Cell Int. 2023;23(1):180. DOI:10.1186/s12935-023-03031-4
4. Sawan C, Herceg Z. Histone modifications and cancer. Adv Genet. 2010;70:57-85. DOI:10.1016/B978-0-12-380866-0.60003-4
5. Gerhauser C. Cancer chemoprevention and nutriepigenetics: state of the art and future challenges. Top Curr Chem. 2013;329:73-132. DOI:10.1007/128_2012_360
6. Kelly TK, De Carvalho DD, Jones PA. Epigenetic modifications as therapeutic targets. Nat Biotechnol. 2010;28(10):1069-78. DOI:10.1038/nbt.1678
7. Banerjee S, Kong D, Wang Z, et al. Attenuation of multi-targeted proliferation-linked signaling by 3,3’-diindolylmethane (DIM): from bench to clinic. Mutat Res. 2011;728(1-2):47-66. DOI:10.1016/j.mrrev.2011.06.001
8. Reed GA, Arneson DW, Putnam WC, et al. Single-dose and multiple-dose administration of indole-3-carbinol to women: pharmacokinetics based on 3,3’-diindolylmethane. Cancer Epidemiol Biomarkers Prev. 2006;15(12):2477-81. DOI:10.1158/1055-9965.EPI-06-0396
9. Reed GA, Sunega JM, Sullivan DK, et al. Single-dose pharmacokinetics and tolerability of absorption-enhanced 3,3’-diindolylmethane in healthy subjects. Cancer Epidemiol Biomarkers Prev. 2008;17(10):2619-24. DOI:10.1158/1055-9965.EPI-08-0520
10. Heath EI, Heilbrun LK, Li J, et al. A phase I dose-escalation study of oral BR-DIM (BioResponse 3,3'-diindolylmethane) in castrate-resistant, non-metastatic prostate cancer. Am J Transl Res. 2010;2(4):402-11.
11. Dalessandri KM, Firestone GL, Fitch MD, et al. Pilot study: effect of 3,3’-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer. 2004;50(2):161-7. DOI:10.1207/s15327914nc5002_5
12. Parkin DR, Lu Y, Bliss RL, Malejka-Giganti D. Inhibitory effects of a dietary phytochemical 3,3’-diindolylmethane on the phenobarbital-induced hepatic CYP mRNA expression and CYP-catalyzed reactions in female rats. Food Chem Toxicol. 2008;46(7):2451-8. DOI:10.1016/j.fct.2008.03.029
13. Vivar OI, Saunier EF, Leitman DC, et al. Selective activation of estrogen receptor-beta target genes by 3,3’-diindolylmethane. Endocrinology. 2010;151(4):1662-7.
DOI:10.1210/en.2009-1028
14. Shilpa G, Lakshmi S, Jamsheena V, et al. Studies on the mode of action of synthetic diindolylmethane derivatives against triple negative breast cancer cells. Basic Clin Pharmacol Toxicol. 2022;131(4):224-40. DOI:10.1111/bcpt.13767
15. Thomson CA, Chow HHS, Wertheim BC, et al. A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen. Breast Cancer Res Treat. 2017;165(1):97-107. DOI:10.1007/s10549-017-4292-7
16. Hwang C, Sethi S, Heilbrun LK, et al. Anti-androgenic activity of absorption-enhanced 3,3’-diindolylmethane in prostatectomy patients. Am J Transl Res. 2016;8(1):166-76.
17. Shanmugam MK, Arfuso F, Sng JC, et al. Epigenetic Effects of Curcumin in Cancer Prevention. In: Epigenetics of Cancer Prevention. Elsevier. 2019.
DOI:10.1016/B978-0-12-812494-9.00005-6
18. Li Y, Li X, Guo B. Chemopreventive agent 3,3’-diindolylmethane selectively induces proteasomal degradation of class I histone deacetylases. Cancer Res. 2010;70(2):646-54. DOI:10.1158/0008-5472.CAN-09-1924
19. Li XJ, Park ES, Park MH, Kim SM. 3,3’-Diindolylmethane suppresses the growth of gastric cancer cells via activation of the Hippo signaling pathway. Oncol Rep. 2013;30(5):2419-26. DOI:10.3892/or.2013.2717
20. Biersack B. 3,3’-Diindolylmethane and its derivatives: nature-inspired strategies tackling drug resistant tumors by regulation of signal transduction, transcription factors and microRNAs. Cancer Drug Resist. 2020;3(4):867-78. DOI:10.20517/cdr.2020.53
21. Киселев В.И., Алахов В.Ю., Семов А.Б., и др. 3,3’-дииндолилметан – селективный ингибитор активности опухолевых стволовых клеток. Молекулярная медицина. 2012;4 [Kiselev VI, Alakhov VIu, Semov AB., et al. 3,3’-diindolylmethane is a selective inhibitor of cancer stem cells activity. Molekular Medicine. 2012;4 (in Russian)].
22. Xu J, Qi G, Wang W, Sun XS. Advances in 3D peptide hydrogel models in cancer research. NPJ Sci Food. 2021;5(1):14. DOI:10.1038/s41538-021-00096-1
23. Elackattu AP, Feng L, Wang Z. A controlled safety study of diindolylmethane in the immature rat model. Laryngoscope. 2009;119(9):1803-8. DOI:10.1002/lary.20526
24. National Toxicology Program. Toxicology studies of indole-3-carbinol in F344/N rats and B6C3F1/N mice and toxicology and carcinogenesis studies of indole-3-carbinol in Harlan Sprague Dawley rats and B6C3F1/N mice (gavage studies). Natl Toxicol Program Tech Rep Ser. 2017;(584). DOI:10.22427/NTP-TR-584
25. European Commission. EU Novel food catalogue. Available at: https://webgate.ec.europa.eu/fip/novel_food_catalogue. Accessed: 16.07.2024.
________________________________________________
1. Kiselev VI, Ashrafyan LA, Bezhenar VF, Tsypurdeyeva AA. Chemoprevention as a way to control epigenetic changes (analytical review of the literature). Journal of Obstetrics and Women’s Diseases. 2014;63(4):74-9 (in Russian). DOI:10.17816/JOWD63474-79
2. Yakushevskaya OV, Iurova MV. Modulation of epigenetic changes and chemoprophylaxis: 3,3’-diindolylmathane. Women’s Health and Reproduction. 2023;6(61):35-47 (in Russian). DOI:10.31550/2712-85982023-6-4-ZhZiR
3. Reyes-Hernández OD, Figueroa-González G, Quintas-Granados LI, et al. 3,3’-Diindolylmethane and indole-3-carbinol: potential therapeutic molecules for cancer chemoprevention and treatment via regulating cellular signaling pathways. Cancer Cell Int. 2023;23(1):180. DOI:10.1186/s12935-023-03031-4
4. Sawan C, Herceg Z. Histone modifications and cancer. Adv Genet. 2010;70:57-85. DOI:10.1016/B978-0-12-380866-0.60003-4
5. Gerhauser C. Cancer chemoprevention and nutriepigenetics: state of the art and future challenges. Top Curr Chem. 2013;329:73-132. DOI:10.1007/128_2012_360
6. Kelly TK, De Carvalho DD, Jones PA. Epigenetic modifications as therapeutic targets. Nat Biotechnol. 2010;28(10):1069-78. DOI:10.1038/nbt.1678
7. Banerjee S, Kong D, Wang Z, et al. Attenuation of multi-targeted proliferation-linked signaling by 3,3’-diindolylmethane (DIM): from bench to clinic. Mutat Res. 2011;728(1-2):47-66. DOI:10.1016/j.mrrev.2011.06.001
8. Reed GA, Arneson DW, Putnam WC, et al. Single-dose and multiple-dose administration of indole-3-carbinol to women: pharmacokinetics based on 3,3’-diindolylmethane. Cancer Epidemiol Biomarkers Prev. 2006;15(12):2477-81. DOI:10.1158/1055-9965.EPI-06-0396
9. Reed GA, Sunega JM, Sullivan DK, et al. Single-dose pharmacokinetics and tolerability of absorption-enhanced 3,3’-diindolylmethane in healthy subjects. Cancer Epidemiol Biomarkers Prev. 2008;17(10):2619-24. DOI:10.1158/1055-9965.EPI-08-0520
10. Heath EI, Heilbrun LK, Li J, et al. A phase I dose-escalation study of oral BR-DIM (BioResponse 3,3'-diindolylmethane) in castrate-resistant, non-metastatic prostate cancer. Am J Transl Res. 2010;2(4):402-11.
11. Dalessandri KM, Firestone GL, Fitch MD, et al. Pilot study: effect of 3,3’-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer. 2004;50(2):161-7. DOI:10.1207/s15327914nc5002_5
12. Parkin DR, Lu Y, Bliss RL, Malejka-Giganti D. Inhibitory effects of a dietary phytochemical 3,3’-diindolylmethane on the phenobarbital-induced hepatic CYP mRNA expression and CYP-catalyzed reactions in female rats. Food Chem Toxicol. 2008;46(7):2451-8. DOI:10.1016/j.fct.2008.03.029
13. Vivar OI, Saunier EF, Leitman DC, et al. Selective activation of estrogen receptor-beta target genes by 3,3’-diindolylmethane. Endocrinology. 2010;151(4):1662-7.
DOI:10.1210/en.2009-1028
14. Shilpa G, Lakshmi S, Jamsheena V, et al. Studies on the mode of action of synthetic diindolylmethane derivatives against triple negative breast cancer cells. Basic Clin Pharmacol Toxicol. 2022;131(4):224-40. DOI:10.1111/bcpt.13767
15. Thomson CA, Chow HHS, Wertheim BC, et al. A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen. Breast Cancer Res Treat. 2017;165(1):97-107. DOI:10.1007/s10549-017-4292-7
16. Hwang C, Sethi S, Heilbrun LK, et al. Anti-androgenic activity of absorption-enhanced 3,3’-diindolylmethane in prostatectomy patients. Am J Transl Res. 2016;8(1):166-76.
17. Shanmugam MK, Arfuso F, Sng JC, et al. Epigenetic Effects of Curcumin in Cancer Prevention. In: Epigenetics of Cancer Prevention. Elsevier. 2019.
DOI:10.1016/B978-0-12-812494-9.00005-6
18. Li Y, Li X, Guo B. Chemopreventive agent 3,3’-diindolylmethane selectively induces proteasomal degradation of class I histone deacetylases. Cancer Res. 2010;70(2):646-54. DOI:10.1158/0008-5472.CAN-09-1924
19. Li XJ, Park ES, Park MH, Kim SM. 3,3’-Diindolylmethane suppresses the growth of gastric cancer cells via activation of the Hippo signaling pathway. Oncol Rep. 2013;30(5):2419-26. DOI:10.3892/or.2013.2717
20. Biersack B. 3,3’-Diindolylmethane and its derivatives: nature-inspired strategies tackling drug resistant tumors by regulation of signal transduction, transcription factors and microRNAs. Cancer Drug Resist. 2020;3(4):867-78. DOI:10.20517/cdr.2020.53
21. Kiselev VI, Alakhov VIu, Semov AB., et al. 3,3’-diindolylmethane is a selective inhibitor of cancer stem cells activity. Molekular Medicine. 2012;4 (in Russian).
22. Xu J, Qi G, Wang W, Sun XS. Advances in 3D peptide hydrogel models in cancer research. NPJ Sci Food. 2021;5(1):14. DOI:10.1038/s41538-021-00096-1
23. Elackattu AP, Feng L, Wang Z. A controlled safety study of diindolylmethane in the immature rat model. Laryngoscope. 2009;119(9):1803-8. DOI:10.1002/lary.20526
24. National Toxicology Program. Toxicology studies of indole-3-carbinol in F344/N rats and B6C3F1/N mice and toxicology and carcinogenesis studies of indole-3-carbinol in Harlan Sprague Dawley rats and B6C3F1/N mice (gavage studies). Natl Toxicol Program Tech Rep Ser. 2017;(584). DOI:10.22427/NTP-TR-584
25. European Commission. EU Novel food catalogue. Available at: https://webgate.ec.europa.eu/fip/novel_food_catalogue. Accessed: 16.07.2024.
Авторы
А.В. Власов1, О.В. Якушевская*2
1ФГАОУ ВО «Российский университет дружбы народов им. Патриса Лумумбы», Москва, Россия;
2ФГБУ «Национальный медицинский исследовательский центр акушерства, гинекологии и перинатологии им. акад. В.И. Кулакова» Минздрава России, Москва, Россия
*aluckyone777@gmail.com
1ФГАОУ ВО «Российский университет дружбы народов им. Патриса Лумумбы», Москва, Россия;
2ФГБУ «Национальный медицинский исследовательский центр акушерства, гинекологии и перинатологии им. акад. В.И. Кулакова» Минздрава России, Москва, Россия
*aluckyone777@gmail.com
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Andrei V. Vlasov1, Oksana V. Yakushevskaya*2
1Patrice Lumumba People’s Friendship University of Russia, Moscow, Russia;
2Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
*aluckyone777@gmail.com
Цель портала OmniDoctor – предоставление профессиональной информации врачам, провизорам и фармацевтам.