Buy (150 RUB)
Generate QR code
Open Access
Subscription or Fee Access
Molecular mechanisms of action of DIM and its clinical application
E. A. Nikitina,
S. V. Orlova,
T. T. Batysheva,
N. V. Balashova,
M. V. Alekseeva,
A. N. Vodolazkaya,
E. V. Prokopenko,
Kh. A. Magomedova https://doi.org/10.33667/2078-5631-2024-19-9-15
Abstract
Optimal nutrition requires complete provision of the human needs not only for energy, macro- and micronutrients, but also for minor biologically active substances. Some of the most promising chemoprotectors are glucosinolates and their active derivatives, such as 3,3’-diindolylmethane (DIM). DIM has the ability to inhibit the development and progression of neoplasia by regulating multiple intracellular signaling pathways. Currently, the clinical efficacy of DIM is being studied in breast and prostate cancer, and the possibility of using DIM’s antioxidant and anti-inflammatory properties in neurodegenerative, metabolic and immune diseases is being investigated.
About the Authors
E. A. Nikitina
Peoples’ Friendship University of Russia named after Patrice Lumumba; Scientific and Practical Center for Pediatric Psychoneurology of the Moscow Department of Health; National Medical Research Center for Therapy and Preventive Medicine
Russian Federation
Russian Federation
Nikitina Elena A., PhD Med, associate professor at Dept of Dietetics and Clinical
Nutrition; Research Fellow; Expert of the Methodological Accreditation and
Simulation Center
Moscow
S. V. Orlova
Peoples’ Friendship University of Russia named after Patrice Lumumba; Scientific and Practical Center for Pediatric Psychoneurology of the Moscow Department of Health
Russian Federation
Russian Federation
Orlova Svetlana V., DM Sci (habil.), professor, head of Dept of Dietetics
and Clinical Nutritiology; Chief Researcher
Moscow
T. T. Batysheva
Peoples’ Friendship University of Russia named after Patrice Lumumba; Scientific and Practical Center for Pediatric Psychoneurology of the Moscow Department of Health
Russian Federation
Russian Federation
Batysheva Tatyana T., chief pediatric neurologist of the Health Dept of the City of Moscow, chief pediatric specialist in medical rehabilitation of the Ministry of Health of the Russian Federation, head of Dept of Neurology, Physical, Rehabilitation Medicine and Psychology of Childhood; DM Sci (habil.), professor, Honored Doctor of the Russian Federation, director
Moscow
N. V. Balashova
Peoples’ Friendship University of Russia named after Patrice Lumumba; National Medical Research Center for Therapy and Preventive Medicine
Russian Federation
Russian Federation
Balashova Natalya V., PhD Bio Sci, assistant professor at Dept of Dietetics and Clinical Nutritiology; assistant professor at Dept of Clinical Laboratory Diagnostics of the Faculty of Advanced Training of Doctors
Author ID: 832745
Moscow
M. V. Alekseeva
Peoples’ Friendship University of Russia named after Patrice Lumumba; Scientific and Practical Center for Pediatric Psychoneurology of the Moscow Department of Health
Russian Federation
Russian Federation
Alekseeva Marina.V., PhD Med, deputy director for Organizational and Methodological Work
Moscow
A. N. Vodolazkaya
Austrian Clinic of Micronutrient Therapy Biogena
Russian Federation
Russian Federation
Vodolazkaya Angelina N., dietitian
Moscow
E. V. Prokopenko
INVITRO LLC
Russian Federation
Russian Federation
Prokopenko Elena V., endocrinologist, dietitian
Moscow
Kh. A. Magomedova
Ltd Takem & Co
Russian Federation
Russian Federation
Magomedova Khadizhat A., provizor, general director
Moscow
References
1. Noncommunicable diseases. WHO. https://www.who.int/news-room/fact-sheets/detail/noncommunicable-diseases
2. Breast cancer. World Health Organization (WHO). 13 March 2024 https://www.who.int/news-room/fact-sheets/detail/breast-cancer
3. Healthcare in Russia. 2023: Statistical Collection/Rosstat. M., 2023. 179 p. https://rosstat.gov.ru/storage/mediabank/Zdravoohran-2023.pdf
4. Methodical recommendations MR 2.3.1.0253–21 “Norms of physiological requirements in energy and nutrients of various groups of the population of the Russian Federation”, approved by the Head of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing Chief State Sanitary Physician of the Russian Federation 22.07.2021. (In Russ.). https://www.rospotrebnadzor.ru/documents/details.php?ELEMENT_ID=18979
5. Kim Y, Je Y. Tea consumption and the risks of all-cause, cardiovascular disease, and cancer mortality: a meta-analysis of 38 prospective cohort data sets. Epidemiol Health. 2024 Jun; 21: e2024056. DOI: 10.4178/epih.e2024056
6. Wang K, Li Z, He J. Association of caffeine consumption with all-cause and cause-specific mortality in adult Americans with hypertension. Food Sci Nutr. 2024 Mar 8; 12 (6): 4185–4195. DOI: 10.1002/fsn3.4079
7. Borghi C, Tsioufis K, Agabiti-Rosei E, Burnier M, Cicero AFG, Clement D, Coca A, Desideri G, Grassi G, Lovic D, Lurbe E, Kahan T, Kreutz R, Jelakovic B, Polonia J, Redon J, Van De Borne P, Mancia G. Nutraceuticals and blood pressure control: a European Society of Hypertension position document. J. Hypertens. 2020 May; 38 (5): 799–812. DOI: 10.1097/HJH.0000000000002353
8. Chan KY, Wong MMH, Pang SSH, Lo KKH. Dietary supplementation for gestational diabetes prevention and management: a meta-analysis of randomized controlled trials. Arch Gynecol Obstet. 2021 Jun; 303 (6): 1381–1391. DOI: 10.1007/s00404‑021‑06023‑9
9. Guan R, Van Le Q, Yang H, Zhang D, Gu H, Yang Y, Sonne C, Lam SS, Zhong J, Jianguang Z, Liu R, Peng W. A review of dietary phytochemicals and their relation to oxidative stress and human diseases. Chemosphere. 2021 May; 271: 129499. DOI: 10.1016/j.chemosphere.2020.129499
10. Osadnik T, Goławski M, Lewandowski P, Morze J, Osadnik K, Pawlas N, Lejawa M, Jakubiak GK, Mazur A, Schwingschackl L, Gąsior M, Banach M. A network meta-analysis on the comparative effect of nutraceuticals on lipid profile in adults. Pharmacol Res. 2022 Sep; 183: 106402. DOI: 10.1016/j.phrs.2022.106402
11. Rosell M, Fadnes LT. Vegetables, fruits, and berries – a scoping review for Nordic Nutrition Recommendations 2023. Food Nutr Res. 2024 Jan 25; 68. DOI: 10.29219/fnr.v68.10455
12. Rodríguez-Negrete EV, Morales-González Á, Madrigal-Santillán EO, Sánchez-Reyes K, Álvarez-González I, Madrigal-Bujaidar E, Valadez-Vega C, Chamorro-Cevallos G, Garcia-Melo LF, Morales-González JA. Phytochemicals and Their Usefulness in the Maintenance of Health. Plants (Basel). 2024 Feb 15; 13 (4): 523. DOI: 10.3390/plants13040523
13. Sazali S, Badrin S, Norhayati MN, Idris NS. Coenzyme Q10 supplementation for prophylaxis in adult patients with migraine-a meta-analysis. BMJ Open. 2021 Jan 5; 11 (1): e039358. DOI: 10.1136/bmjopen‑2020–039358
14. An P, Wan S, Luo Y, Luo J, Zhang X, Zhou S, Xu T, He J, Mechanick JI, Wu WC, Ren F, Liu S. Micronutrient Supplementation to Reduce Cardiovascular Risk. J. Am. Coll. Cardiol. 2022 Dec 13; 80 (24): 2269–2285. DOI: 10.1016/j.jacc.2022.09.048
15. Moretti C, Bonomi M, Dionese P, Federici S, Fulghesu AM, Giannelli J, Giordano R, Guccione L, Maseroli E, Moghetti P, Mioni R, Pivonello R, Sabbadin C, Scaroni C, Tonacchera M, Verde N, Vignozzi L, Gambineri A. Inositols and female reproduction disorders: a consensus statement from the working group of the Club of the Italian Society of Endocrinology (SIE)-Women’s Endocrinology. J. Endocrinol Invest. 2024 Jul 15. DOI: 10.1007/s40618–024–02363-w
16. Wei P, Liu M, Chen Y, Chen DC. Systematic review of soy isoflavone supplements on osteoporosis in women. Asian Pac J. Trop Med. 2012 Mar; 5 (3): 243–8. DOI: 10.1016/S 1995–7645 (12) 60033‑9
17. Singla RK, Wang X, Gundamaraju R, Joon S, Tsagkaris C, Behzad S, Khan J, Gautam R, Goyal R, Rakmai J, Dubey AK, Simal-Gandara J, Shen B. Natural products derived from medicinal plants and microbes might act as a game-changer in breast cancer: a comprehensive review of preclinical and clinical studies. Crit Rev Food Sci Nutr. 2023 Nov; 63 (33): 11880–11924. DOI: 10.1080/10408398.2022.2097196
18. Steinbrecher A, Linseisen J. Dietary intake of individual glucosinolates in participants of the EPIC-Heidelberg cohort study. Ann Nutr Metab. 2009; 54 (2): 87–96. DOI: 10.1159/000209266
19. Reyes-Hernández OD, Figueroa-González G, Quintas-Granados LI, Gutiérrez-Ruíz SC, Hernández-Parra H, Romero-Montero A, Del Prado-Audelo ML, Bernal-Chavez SA, Cortés H, Peña-Corona SI, Kiyekbayeva L, Ateşşahin DA, Goloshvili T, Leyva-Gómez G, Sharifi-Rad J. 3,3’-Diindolylmethane and indole‑3-carbinol: potential therapeutic molecules for cancer chemoprevention and treatment via regulating cellular signaling pathways. Cancer Cell Int. 2023 Aug 26; 23 (1): 180. DOI: 10.1186/s12935‑023‑03031‑4
20. Denisova E. L., Korolev A. A., Nikitenko E. I., Kirpichenkova E. V., Fetisov R. N., Kozlov V. V., Onishchenko G. G. Hygienic assessment of indoles in the diet of medical students. Voprosy pitaniia [Problems of Nutrition]. 2018; 87 (6): 22–7. DOI: 10.24411/0042‑8833‑2018‑10063 (in Russ.) Available at: https://pubmed.ncbi.nlm.nih.gov/30763487
21. Ramakrishna K, Jain SK, Krishnamurthy S. Pharmacokinetic and Pharmacodynamic Properties of Indole‑3-carbinol in experimental focal ischemic Injury. Eur. J. Drug Metab Pharmacokinet. 2022 DOI: 10.1007/s13318–022–00771-y
22. Williams DE. Indoles Derived From Glucobrassicin: Cancer Chemoprevention by Indole‑3-Carbinol and 3,3’-Diindolylmethane. Front Nutr. 2021 Oct 1; 8: 734334. DOI: 10.3389/fnut.2021.734334
23. Diindolylmethane (DIM) Information Resource Center. An Initiative of Faculty Members and Research Fellows at the University of California at Berkeley https://www.diindolylmethane-dim.com/references.htm
24. Centofanti F, Buono A, Verboni M, Tomino C, Lucarini S, Duranti A, Pandolfi PP, Novelli G. Synthetic Methodologies and Therapeutic Potential of Indole‑3-Carbinol (I3C) and Its Derivatives. Pharmaceuticals (Basel). 2023 Feb 5; 16 (2): 240. DOI: 10.3390/ph16020240
25. Thomson CA, Ho E, Strom MB. Chemopreventive properties of 3,3-diindolylmethane in breast cancer: evidence from experimental and human studies. Nutr Rev. 2016 Jul; 74 (7): 432–43. DOI: 10.1093/nutrit/nuw010
26. Li F, Xu Y, Chen C, Chen SM, Xiao BK, Tao ZZ. Pro-apoptotic and anti-proliferative effects of 3,3’-diindolylmethane in nasopharyngeal carcinoma cells via downregulation of telomerase activity. Mol Med Rep. 2015 Sep; 12 (3): 3815–3820. DOI: 10.3892/mmr.2015.3836
27. Herz C, Tran HTT, Landerer S, Gaus J, Schlotz N, Lehr L, Schäfer WR, Treeck O, Odongo GA, Skatchkov I, Lamy E. Normal human immune cells are sensitive to telomerase inhibition by Brassica-derived 3,3-diindolylmethane, partly mediated via ERα/β-AP1 signaling. Mol Nutr Food Res. 2017 Sep; 61 (9). DOI: 10.1002/mnfr.201600524
28. Kong D, Banerjee S, Huang W, Li Y, Wang Z, Kim HR, Sarkar FH. Mammalian target of rapamycin repression by 3,3’-diindolylmethane inhibits invasion and angiogenesis in platelet-derived growth factor-D-overexpressing PC 3 cells. Cancer Res. 2008 Mar 15; 68 (6): 1927–34. DOI: 10.1158/0008–5472.CAN‑07–3241
29. Chang X, Tou JC, Hong C, Kim HA, Riby JE, Firestone GL, Bjeldanes LF. 3,3’-Diindolylmethane inhibits angiogenesis and the growth of transplantable human breast carcinoma in athymic mice. Carcinogenesis. 2005 Apr; 26 (4): 771–8. DOI: 10.1093/carcin/bgi018
30. Kim EJ, Shin M, Park H, Hong JE, Shin HK, Kim J, Kwon DY, Park JH. Oral administration of 3,3’-diindolylmethane inhibits lung metastasis of 4T1 murine mammary carcinoma cells in BALB/c mice. J. Nutr. 2009 Dec; 139 (12): 2373–9. DOI: 10.3945/jn.109.111864.
31. Li WX, Chen LP, Sun MY, Li JT, Liu HZ, Zhu W. 3'3-Diindolylmethane inhibits migration, invasion and metastasis of hepatocellular carcinoma by suppressing FAK signaling. Oncotarget. 2015 Sep 15; 6 (27): 23776–92. DOI: 10.18632/oncotarget.4196
32. Munakarmi S, Shrestha J, Shin HB, Lee GH, Jeong YJ. 3,3’-Diindolylmethane Suppresses the Growth of Hepatocellular Carcinoma by Regulating Its Invasion, Migration, and ER Stress-Mediated Mitochondrial Apoptosis. Cells. 2021 May 12; 10 (5): 1178. DOI: 10.3390/cells10051178
33. Tsao CW, Li JS, Lin YW, Wu ST, Cha TL, Liu CY. Regulation of carcinogenesis and mediation through Wnt/β-catenin signaling by 3,3’-diindolylmethane in an enzalutamide-resistant prostate cancer cell line. Sci Rep. 2021 Jan 13; 11 (1): 1239. DOI: 10.1038/s41598‑020‑80519‑3
34. Zhu P, Yu H, Zhou K, Bai Y, Qi R, Zhang S. 3,3’-Diindolylmethane modulates aryl hydrocarbon receptor of esophageal squamous cell carcinoma to reverse epithelial-mesenchymal transition through repressing RhoA/ROCK1-mediated COX2/PGE 2 pathway. J Exp Clin Cancer Res. 2020 Jun 16;39(1):113. DOI: 10.1186/s13046–020–01618–7.)
35. Amarakoon D, Lee WJ, Tamia G, Lee SH. Indole‑3-Carbinol: Occurrence, Health-Beneficial Properties, and Cellular/Molecular Mechanisms. Annu Rev Food Sci Technol. 2023 Mar 27; 14: 347–366. DOI: 10.1146/annurev-food‑060721–025531
36. Jayakumar P, Pugalendi KV, Sankaran M. Attenuation of hyperglycemia-mediated oxidative stress by indole‑3-carbinol and its metabolite 3, 3’- diindolylmethane in C 57BL/6J mice. J. Physiol Biochem. 2014 Jun; 70 (2): 525–34. DOI: 10.1007/s13105‑014‑0332‑5
37. Experience in the use of indinol in papillomavirus infection: Sat. articles. Мoscow, 2011. 50 pp. (In Russ.). Available at: https://indinol.ru/assets/files/Sbornik_VPH_A4_out.pdf
38. Nikitina D, Llacuachaqui M, Sepkovic D, Bradlow HL, Narod SA, Kotsopoulos J. The effect of oral 3,3’-diindolylmethane supplementation on the 2:16α-OHE ratio in BRCA1 mutation carriers. Fam Cancer. 2015 Jun; 14 (2): 281–6. DOI: 10.1007/s10689‑015‑9783‑2
39. Godínez-Martínez E, Santillán R, Sámano R, Chico-Barba G, Tolentino MC, Hernández-Pineda J. Effectiveness of 3,3’-Diindolylmethane Supplements on Favoring the Benign Estrogen Metabolism Pathway and Decreasing Body Fat in Premenopausal Women. Nutr Cancer. 2023; 75 (2): 510–519. DOI: 10.1080/01635581.2022.2123535
40. Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF. 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
41. Green T, See J, Schauch M, Reil J, Glover M, Brix J, Gerry A, Li K, Newman M, Gahler RJ, Wood S. A randomized, double-blind, placebo-controlled, cross-over trial to evaluate the effect of EstroSense® on 2-hydroxyestrone:16α-hydroxyestrone ratio in premenopausal women. J. Complement Integr Med. 2022 Oct 6; 20 (1): 199–206. DOI: 10.1515/jcim‑2022–0301
42. Thomson CA, Chow HHS, Wertheim BC, Roe DJ, Stopeck A, Maskarinec G, Altbach M, Chalasani P, Huang C, Strom MB, Galons JP, Thompson PA. A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen. Breast Cancer Res Treat. 2017 Aug; 165 (1): 97–107. DOI: 10.1007/s10549‑017‑4292‑7
43. Yerushalmi R, Bargil S, Ber Y, Ozlavo R, Sivan T, Rapson Y, Pomerantz A, Tsoref D, Sharon E, Caspi O, Grubsrein A, Margel D. 3,3-Diindolylmethane (DIM): a nutritional intervention and its impact on breast density in healthy BRCA carriers. A prospective clinical trial. Carcinogenesis. 2020 Oct 15; 41 (10): 1395–1401. DOI: 10.1093/carcin/bgaa050
44. Сайт «Международная ассоциация по патологии шейки матки и кольпоскопии». URL: https://ifcpc.org/ the International Federation of colposcopy and cervical pathology. https://ifcpc.org
45. Xue L, Pestka JJ, Li M, Firestone GL, Bjeldanes LF. 3,3’-Diindolylmethane stimulates murine immune function in vitro and in vivo. J. Nutr Biochem. 2008 May; 19 (5): 336–44. DOI: 10.1016/j.jnutbio.2007.05.004
46. Verma V, Sharma V, Singh V, Sharma S, Bishnoi AK, Chandra V, Maikhuri JP, Dwivedi A, Kumar A, Gupta G. Designed modulation of sex steroid signaling inhibits telomerase activity and proliferation of human prostate cancer cells. Toxicol Appl Pharmacol. 2014 Oct 15; 280 (2): 323–34. DOI: 10.1016/j.taap.2014.08.002
47. Heath EI, Heilbrun LK, Li J, Vaishampayan U, Harper F, Pemberton P, Sarkar FH. 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 Jul 23; 2 (4): 402–11. PMID: 20733950; PMCID: PMC 2923864. https://pubmed.ncbi.nlm.nih.gov/20733950
48. Hwang C, Sethi S, Heilbrun LK, Gupta NS, Chitale DA, Sakr WA, Menon M, Peabody JO, Smith DW, Sarkar FH, Heath EI. Anti-androgenic activity of absorption-enhanced 3, 3’-diindolylmethane in prostatectomy patients. Am. J. Transl Res. 2016 Jan 15; 8 (1): 166–76. PMID: 27069550; PMCID: PMC 4759426. https://pubmed.ncbi.nlm.nih.gov/27069550
49. Pilla Reddy V, Jo H, Neuhoff S. Food constituent- and herb-drug interactions in oncology: Influence of quantitative modelling on Drug labelling. Br. J. Clin. Pharmacol. 2021 Oct; 87 (10): 3988–4000. DOI: 10.1111/bcp.14822
50. Chan WJ, Adiwidjaja J, McLachlan AJ, Boddy AV, Harnett JE. Interactions between natural products and cancer treatments: underlying mechanisms and clinical importance. Cancer Chemother Pharmacol. 2023 Feb; 91 (2): 103–119. DOI: 10.1007/s00280-023-04504-z
51. Hussaarts KGAM, Hurkmans DP, Oomen-de Hoop E, van Harten LJ, Berghuis S, van Alphen RJ, Spierings LEA, van Rossum-Schornagel QC, Vastbinder MB, van Schaik RHN, van Gelder T, Jager A, van Leeuwen RWF, Mathijssen RHJ. Impact of Curcumin (with or without Piperine) on the Pharmacokinetics of Tamoxifen. Cancers (Basel). 2019 Mar 22; 11 (3): 403. DOI: 10.3390/cancers11030403
52. Parkin DR, Malejka-Giganti D. Differences in the hepatic P450-dependent metabolism of estrogen and tamoxifen in response to treatment of rats with 3,3’-diindolylmethane and its parent compound indole‑3-carbinol. Cancer Detect Prev. 2004; 28 (1): 72–9. DOI: 10.1016/j.cdp.2003.11.006
53. Kim HW, Kim J, Kim J, Lee S, Choi BR, Han JS, Lee KW, Lee HJ. 3,3’-Diindolylmethane inhibits lipopolysaccharide-induced microglial hyperactivation and attenuates brain inflammation. Toxicol Sci. 2014 Jan; 137 (1): 158–67. DOI: 10.1093/toxsci/kft240
54. Du H, Zhang X, Zeng Y, Huang X, Chen H, Wang S, Wu J, Li Q, Zhu W, Li H, Liu T, Yu Q, Wu Y, Jie L. A Novel Phytochemical, DIM, Inhibits Proliferation, Migration, Invasion and TNF α Induced Inflammatory Cytokine Production of Synovial Fibroblasts From Rheumatoid Arthritis Patients by Targeting MAPK and AKT/mTOR Signal Pathway. Front Immunol. 2019 Jul 23; 10: 1620. DOI: 10.3389/fimmu.2019.01620
55. Ramakrishna K, Singh N, Krishnamurthy S. Diindolylmethane ameliorates platelet aggregation and thrombosis: In silico, in vitro, and in vivo studies. Eur J Pharmacol. 2022 Mar 15; 919: 174812. DOI: 10.1016/j.ejphar.2022.174812
56. Yang H, Seo SG, Shin SH, Min S, Kang MJ, Yoo R, Kwon JY, Yue S, Kim KH, Cheng JX, Kim JR, Park JS, Kim JH, Park JHY, Lee HJ, Lee KW. 3,3’-Diindolylmethane suppresses high-fat diet-induced obesity through inhibiting adipogenesis of pre-adipocytes by targeting USP2 activity. Mol Nutr Food Res. 2017 Oct; 61 (10). DOI: 10.1002/mnfr.201700119
57. Poornima J, Mirunalini S. Regulation of carbohydrate metabolism by indole‑3-carbinol and its metabolite 3,3’-diindolylmethane in high-fat diet-induced C 57BL/6J mice. Mol Cell Biochem. 2014 Jan; 385 (1–2): 7–15. DOI: 10.1007/s11010‑013‑1808‑2
58. Choi KM, Yoo HS. Amelioration of Hyperglycemia-Induced Nephropathy by 3,3’-Diindolylmethane in Diabetic Mice. Molecules. 2019 Dec 6; 24 (24): 4474. DOI: 10.3390/molecules24244474
59.
Review
For citations:
Nikitina E.A., Orlova S.V., Batysheva T.T., Balashova N.V., Alekseeva M.V., Vodolazkaya A.N., Prokopenko E.V., Magomedova Kh.A. Molecular mechanisms of action of DIM and its clinical application. Medical alphabet. 2024;(19):9-15. (In Russ.) https://doi.org/10.33667/2078-5631-2024-19-9-15
Views:
238
Email this article 