Indole carbinol (Indinol Forto) and benign breast diseases in the context of cancer prevention
Kareva E.N.
The use of indole carbinol in the treatment of benign breast diseases has shown potential benefits for preventing the development of neoplasia. The metabolism of indole carbinol begins in the stomach, where a number of biologically active compounds are formed as a result of acid-catalyzed reactions. These compounds include 3,3'-diindolylmethane (DIM) and 5,11-dihydroindolo-[3,2-b]-carbazole (ICZ), which are oligomers. Indole carbinol and DIM, through their own aryl hydrocarbon receptors, regulate the expression of enzymes involved in liver metabolism and the excretion of various biologically active substances, including steroid hormones, medications, carcinogens, and toxins. Preclinical studies have shown that indole carbinol and DIM have indirect anti-estrogenic activity, which may help reduce the risk of hormone-dependent cancer. Indole carbinol and DIM can alter the profile of estradiol metabolites in the urine of women, reducing the number of proliferation-stimulating molecules. Experimental studies have demonstrated that indole carbinol is able to affect several signaling pathways that are inhibited in tumor cells, namely, those that control cell proliferation, apoptosis, migration, invasion and angiogenesis. Thus, indole carbinol can selectively affect altered cells. DIM has lower bioavailability than indole carbinol. Indole carbinol, which is part of the Indinol Forto medication, is included in clinical guidelines for the treatment of benign breast disease.
Conclusion: The mechanisms of action of indole carbinol characterize Indinol Forto as a medication with a potential oncoprotective effect. This result is especially important in terms of preventing breast cancer in patients with cyclic mastalgia.
Conflicts of interest: The author declares lack of the possible conflicts of interest.
Funding: The study was conducted without sponsorship.
For citation: Kareva E.N. Indole carbinol (Indinol Forto) and benign breast diseases in the context of cancer prevention.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2025; (6): 164-170 (in Russian)
https://dx.doi.org/10.18565/aig.2025.162
Keywords
References
- Chen C., Wang Z., Liao Z., Zhang Y., Lei W., Shui X. Aryl hydrocarbon receptor: An emerging player in breast cancer pathogenesis and its potential as a drug target (Review). Mol. Med. Rep. 2024; 29(1): 11. https://dx.doi.org/10.3892/mmr.2023.13134
- Du H., Zhang X., Zeng Y., Huang X., Chen H., Wang S. et al. 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; 10: 1620. https://dx.doi.org/10.3389/fimmu.2019.01620
- Banerjee S., Kong D., Wang Z.., Bao B, Hillman G.G., Sarkar F.H. Attenuation of multi-targeted proliferation-linked signaling by 3,3'-diindolylmethane (DIM): from bench to clinic. Mutat. Res. 2011; 728(1-2): 47-66. https://dx.doi.org/10.1016/j.mrrev.2011.06.001
- Wang M.L., Shih C.K., Chang H.P., Chen Y.H. Antiangiogenic activity of indole-3-carbinol in endothelial cells stimulated with activated macrophages. Food Chem. 2012; 134(2): 811-20. https://dx.doi.org/10.1016/j.foodchem.2012.02.185
- Chang X., Firestone G.L., Bjeldanes L.F. Inhibition of growth factor-induced Ras signaling in vascular endothelial cells and angiogenesis by 3,3'-diindolylmethane. Carcinogenesis. 2006; 27(3): 541-50. https://dx.doi.org/10.1093/carcin/bgi230
- Chen D.Z., Qi M., Auborn K.J., Carter T.H. Indole-3-carbinol and diindolylmethane induce apoptosis of human cervical cancer cells and in murine HPV16-transgenic preneoplastic cervical epithelium. J. Nutr. 2001; 131(12): 3294-302. https://dx.doi.org/10.1093/jn/131.12.3294
- Vezina C.M, Lin T.M., Peterson R.E. AHR signaling in prostate growth, morphogenesis, and disease. Biochem. Pharmacol. 2009; 77(4): 566-76. https://dx.doi.org/10.1016/j.bcp.2008.09.039
- Safe S., Lee S.O., Jin U.H. Role of the aryl hydrocarbon receptor in carcinogenesis and potential as a drug target. Toxicol. Sci. 2013; 135(1):1-16. https://dx.doi.org/10.1093/toxsci/kft128
- Qi M., Anderson A.E., Chen D.Z., Sun S., Auborn K.J. Indole-3-carbinol prevents PTEN loss in cervical cancer in vivo. Mol. Med. 2005; 11(1-12): 59-63. https://dx.doi.org/10.2119/2006-00007.Auborn
- Tamura M., Gu J., Matsumoto K., Aota S., Parsons R., Yamada K.M. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science. 1998; 280(5369): 1614-7. https://dx.doi.org/10.1126/science.280.5369.1614
- Ho J.N., Jun W., Choue R., Lee J. I3C and ICZ inhibit migration by suppressing the EMT process and FAK expression in breast cancer cells. Mol. Med. Rep. 2013; 7(2): 384-8. https://dx.doi.org/10.3892/mmr.2012.1198
- Pani S., Sahoo A., Patra A., Debata P.R. Phytocompounds curcumin, quercetin, indole-3-carbinol, and resveratrol modulate lactate-pyruvate level along with cytotoxic activity in HeLa cervical cancer cells. Biotechnol. Appl. Biochem. 2021; 68(6): 1396-402. https://dx.doi.org/10.1002/bab.2061
- Lopez-Vazquez A., Garcia-Banuelos J.J., Gonzalez-Garibay A.S., Urzua-Lozano P.E., Del Toro-Arreola S., Bueno-Topete M.R. et al. IRS-1 pY612 and Akt-1/PKB pT308 phosphorylation and antiinflammatory effect of diindolylmethane in adipocytes cocultured with macrophages. Med. Chem. 2017; 13(8): 727-33. https://dx.doi.org/10.2174/1573406413666170922095011
- Chichai A.S., Popova T.N., Kryl'skii E.D., Oleinik S.A., Razuvaev G.A. Indole-3-carbinol mitigates oxidative stress and inhibits inflammation in rat cerebral ischemia/reperfusion model. Biochimie. 2023; 213: 1-11. https://dx.doi.org/10.1016/j.biochi.2023.04.018
- Srikanth Y., Julius T., Gayathri M., Tuyishime H.S., Gelege M.D., Kumar S.S. et al. Indole 3 carbinol attenuated memory impairment, oxidative stress, inflammation, and apoptosis in bilateral common carotid artery occlusion induced brain damage in rats. 3Biotech. 2025; 15(2): 51. https://dx.doi.org/10.1007/s13205-024-04199-w
- Madison C.A., Hillbrick L., Kuempel J., Albrecht G.L., Landrock K.K., Safe S. et al. Intestinal epithelium aryl hydrocarbon receptor is involved in stress sensitivity and maintaining depressive symptoms. Behav. Brain Res. 2023; 440: 114256. https://dx.doi.org/10.1016/j.bbr.2022.114256
- Qazi A., Comiskey S., Calzadilla N., Amin F., Sharma A., Khin E. et al. Potential dietary and therapeutic strategies involving indole-3-carbinole in preclinical models of intestinal inflammation. Nutrients. 2023; 15(23): 4980. https://dx.doi.org/10.3390/nu15234980
- Ramakrishna K., Sinku S., Majumdar S., Singh N., Gajendra T.A., Rani A. et al. Indole-3-carbinol ameliorated the thioacetamide-induced hepatic encephalopathy in rats. Toxicology. 2023; 492: 153542. https://dx.doi.org/10.1016/j.tox.2023.153542
- Holloman B.L., Wilson K., Cannon A., Nagarkatti M., Nagarkatti P.S. Indole-3-carbinol attenuates lipopolysaccharide-induced acute respiratory distress syndrome through activation of AhR: role of CCR2+ monocyte activation and recruitment in the regulation of CXCR2+ neutrophils in the lungs. Front. Immunol. 2024; 15: 1330373. https://dx.doi.org/10.3389/fimmu.2024.1330373
- Baez-Gonzalez A.S., Carrazco-Carrillo J.A., Figueroa-Gonzalez G., Quintas-Granados L.I., Padilla-Benavides T., Reyes-Hernandez O.D. Functional effect of indole-3 carbinol in the viability and invasive properties of cultured cancer cells. Biochem. Biophys. Rep. 2023; 35: 101492. https://dx.doi.org/10.1016/j.bbrep.2023.101492
- Paltsev M., Kiselev V., Drukh V., Muyzhnek E., Kuznetsov I., Andrianova E. et al. First results of the double-blind randomized placebo-controlled multicenter clinical trial of DIM-based therapy designed as personalized approach to reverse prostatic intraepithelial neoplasia (PIN). EPMA J. 2016; 7(1): 5. https://dx.doi.org/10.1186/s13167-016-0057-3
- Thomson C.A., Chow H.H.S., Wertheim B.C., Roe D.J., Stopeck A., Maskarinec G. 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. https://dx.doi.org/10.1007/s10549-017-4292-7
- 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): NTP-TR-584. https://dx.doi.org/10.22427/NTP-TR-584
- Reyes-Hernández O.D., Figueroa-González G., Quintas-Granados L.I., Gutiérrez-Ruíz S.C., Hernández-Parra H., Romero-Montero A. 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. https://dx.doi.org/10.1186/s12935-023-03031-4
- Dalessandri K.M., Firestone G.L., Fitch M.D., Bradlow H.L., Bjeldanes L.F. 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. https://dx.doi.org/10.1207/s15327914nc5002_5
- Киселев В.И., Сметник В.П., Сутурина Л.В., Селиванов С.П., Рудакова Е.Б., Рахматуллина И.Р., Андреева Е.Н., Фадеева Н.И., Хасанов Р.Ш., Кулагина Н.В., Рожкова Н.И., Артымук Н.В., Гависова А.А., Муйжнек Е.Л., Кузнецов И.Н., Друх В.М. Индолкарбинол (Индинол Форто) – метод мультитаргетной терапии при циклической мастодинии. Акушерство и гинекология. 2013; 7: 56-62. [Kiselev V.I., Smetnik V.P., Suturina L.V., Selivanov S.P., Rudakova E.B., Rakhmatullina I.R., Andreyeva E.N., Fadeyeva N.I., Khasanov R.Sh., Kulagina N.V., Rozhkova N.I., Artymuk N.V., Gavisova A.A., Muizhnek E.L., Kuznetsov I.N., Drukh V.M. Indole carbinol (Indinol Forto) is a multitargeted therapy option for cyclic mastodynia. Obstetrics and Gynecology. 2013; (7): 56-62 (in Russian)].
- Родионов В.В., Сметник А.А., Сенча А.Н., Кометова В.В., Бикеев Ю.В., Ашрафян Л.А. Алгоритм диагностики и лечения доброкачественной дисплазии молочной железы. Акушерство и гинекология. 2022; 6(Приложение): 23-34. [Rodionov V.V., Smetnik A.A., Sencha A.N., Kometova V.V., Bikeev Yu.V., Ashrafyan L.A. Algorithm for diagnosis and treatment of benign breast dysplasia. Obstetrics and Gynecology. 2022; 6(Suppl.): 23-34 (in Russian)].
- Общая характеристика лекарственного препарата Индинол Форто. ЛП-N=(007558)-(РГ-RU) от 05.11.2024. [General characteristics of the drug product Indinol Forto. LP-N=(007558)-(РГ-RU) from 05.11.2024. (in Russian)].
Received 19.06.2025
Accepted 25.06.2025