Progress in the anti-tumor effects of indole-3-carbinol

doi:10.16139/j.1007-9610.2026.02.11

Abstract

Abstract:

In recent years, indole-3-carbinol (I3C) has been introduced into tumor therapy research, playing a key role in inhibiting and interfering with the occurrence and development of various tumors. This article explored the mechanisms by which I3C and its indole-derived metabolite, 3, 3’-diindolylmethane (DIM), which is converted in the acidic environment of the stomach, serve as effective natural chemopreventive agents against multiple tumors. The physicochemical properties of I3C were presented alongside epidemiological studies, emphasizing its safety and efficacy. Furthermore, it provided a detail discussion of the molecular mechanisms of I3C's anti-tumor effects, including various signaling pathways such as the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin [PI3K/PKB(AKT)/mTOR] and aryl hydrocarbon receptor (AHR) pathways. This article served as a valuable reference for further research on I3C.

Key words: Indole-3-carbinol(I3C), Phosphoinositide 3-kinase/protein kinase B [PI3K/PKB(AKT) pathway], Aryl hydrocarbon receptor(AHR), Anti-tumor

CLC Number:

WANG Guimin, FAN Hao, ZHOU Leqi, WEN Rongbo, YU Guanyu, HAO Liqaing, ZHANG Wei. Progress in the anti-tumor effects of indole-3-carbinol[J]. Journal of Surgery Concepts & Practice, 2026, 31(02): 163-168.

References 50

[1]	KATZ E, NISANI S, CHAMOVITZ D A. Indole-3-carbinol: a plant hormone combatting cancer[J]. F1000Res, 2018,7:F1000 Faculty Rev-689.
[2]	AHMAD A, BIERSACK B, LI Y, et al. Targeted regulation of PI3K/AKT/mTOR/NF-κB signaling by indole compounds and their derivatives: mechanistic details and biological implications for cancer therapy[J]. Anticancer Agents Med Chem, 2013, 13(7):1002-1013. doi: 10.2174/18715206113139990078 URL
[3]	SHAPIRO T A, FAHEY J W, WADE K L, et al. Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables[J]. Cancer Epidemiol Biomarkers Prev, 1998, 7(12):1091-1100.
[4]	HERR I, BUCHLER M W. Dietary constituents of broccoli and other cruciferous vegetables: implications for prevention and therapy of cancer[J]. Cancer Treat Rev, 2010, 36(5):377-383. doi: 10.1016/j.ctrv.2010.01.002 pmid: 20172656
[5]	BAEZ-GONZALEZ A S, CARRAZCO-CARRILLO J A, FIGUEROA-GONZALEZ G, et al. Functional effect of indole-3 carbinol in the viability and invasive properties of cultured cancer cells[J]. Biochem Biophys Rep, 2023,35:101492.
[6]	BRADFIELD C A, BJELDANES L F. Structure-activity relationships of dietary indoles: a proposed mechanism of action as modifiers of xenobiotic metabolism[J]. J Toxicol Environ Health, 1987, 21(3):311-323. doi: 10.1080/15287398709531021 URL
[7]	DASHWOOD R H, FONG A T, ARBOGAST D N, et al. Anticarcinogenic activity of indole-3-carbinol acid products: ultrasensitive bioassay by trout embryo microinjection[J]. Cancer Res, 1994, 54(13):3617-3619. pmid: 8012989
[8]	DASHWOOD R H, UYETAKE L, FONG A T, et al. In vivo disposition of the natural anti-carcinogen indole-3-carbinol after po administration to rainbow trout[J]. Food Chem Toxicol, 1989, 27(6):385-392. doi: 10.1016/0278-6915(89)90144-0 URL
[9]	AMARAKOON D, LEE W J, TAMIA G, et al. Indole-3-carbinol: occurrence, health-beneficial properties, and cellular/molecular mechanisms[J]. Annu Rev Food Sci Technol, 2023,14:347-366.
[10]	POPOLO A, PINTO A, DAGLIA M, et al. Two likely targets for the anti-cancer effect of indole derivatives from cruciferous vegetables: PI3K/AKT/mTOR signalling pathway and the aryl hydrocarbon receptor[J]. Semin Cancer Biol, 2017,46:132-137.
[11]	SHAW R J, CANTLEY L C. Ras, PI(3)K and mTOR signalling controls tumour cell growth[J]. Nature, 2006, 441(7092):424-430. doi: 10.1038/nature04869
[12]	WENDEL H G, DE STANCHINA E, FRIDMAN J S, et al. Survival signalling by AKT and eIF4E in oncogenesis and cancer therapy[J]. Nature, 2004, 428(6980):332-337. doi: 10.1038/nature02369
[13]	TEE A R, FINGAR D C, MANNING B D, et al. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling[J]. Proc Natl Acad Sci USA, 2002, 99(21):13571-13576. doi: 10.1073/pnas.202476899 pmid: 12271141
[14]	CHUANG H Y, HSU L Y, PAN C M, et al. The E3 ubi-quitin ligase NEDD4-1 mediates temozolomide-resistant glioblastoma through PTEN attenuation and redox imbalance in Nrf2-HO-1 Axis[J]. Int J Mol Sci, 2021, 22(19):10247. doi: 10.3390/ijms221910247 URL
[15]	CHEN H, GAO B, LI J, et al. Indole-3-carbinol prevented tumor progression and potentiated PD1ab therapy by upregulating PTEN in colorectal cancer[J]. Discov Oncol, 2025, 16(1):224. doi: 10.1007/s12672-025-01887-8 pmid: 39985695
[16]	QIAN X, MELKAMU T, UPADHYAYA P, et al. Indole-3-carbinol inhibited tobacco smoke carcinogen-induced lung adenocarcinoma in A/J mice when administered during the post-initiation or progression phase of lung tumorigenesis[J]. Cancer Letters, 2011, 311(1):57-65. doi: 10.1016/j.canlet.2011.06.023 pmid: 21767909
[17]	MAO C G, TAO Z Z, CHEN Z H E, et al. Indole-3-carbinol inhibits nasopharyngeal carcinoma cell growth in vivo and in vitro through inhibition of the PI3K/AKT pathway[J]. Exp Ther Med, 2014, 8(1):207-212. doi: 10.3892/etm.2014.1696 URL
[18]	WANG Y Q, CHEN C, CHEN Z H E, et al. Indole-3-carbinol inhibits cell proliferation and induces apoptosis in Hep-2 laryngeal cancer cells[J]. Oncol Rep, 2013, 30(1):227-233. doi: 10.3892/or.2013.2411 URL
[19]	ZHU J, LI Y, GUAN C, et al. Anti-proliferative and pro-apoptotic effects of 3,3′-diindolylmethane in human cervical cancer cells[J]. Oncol Rep, 2012, 28(3):1063-1068. doi: 10.3892/or.2012.1877 URL
[20]	MENG R Y, LI C S, HU D, et al. Inhibition of the interaction between Hippo/YAP and AKT signaling with ursolic acid and 3'3-diindolylmethane suppresses esophageal cancer tumorigenesis[J]. Korean J Physiol Pharmacol, 2023, 27(5):493-511. doi: 10.4196/kjpp.2023.27.5.493 URL
[21]	NAKAMURA Y, YOGOSAWA S, IZUTANI Y, et al. A combination of indol-3-carbinol and genistein synergistically induces apoptosis in human colon cancer HT-29 cells by inhibiting AKT phosphorylation and progression of autophagy[J]. Mol Cancer, 2009,8:100.
[22]	SKINNER H D, ZHENG J Z, FANG J, et al. Vascular endothelial growth factor transcriptional activation is mediated by hypoxia-inducible factor 1alpha, HDM2, and p70S6K1 in response to phosphatidylinositol 3-kinase/AKT signaling[J]. J Biol Chem, 2004, 279(44):45643-45651. doi: 10.1074/jbc.M404097200 pmid: 15337760
[23]	WANG M L, SHIH C K, CHANG H P, et al. Antiangiogenic activity of indole-3-carbinol in endothelial cells stimulated with activated macrophages[J]. Food Chem, 2012, 134(2):811-820. doi: 10.1016/j.foodchem.2012.02.185 URL
[24]	HAJRA S, PATRA A R, BASU A, et al. Indole-3-carbinol (I3C) enhances the sensitivity of murine breast adenocarcinoma cells to doxorubicin (DOX) through inhibition of NF-κβ, blocking angiogenesis and regulation of mitochondrial apoptotic pathway[J]. Chem Biol Interact, 2018,290:19-36.
[25]	SADDIQ A A, EL-FAR A H, MOHAMED ABDULLAH S A, et al. Curcumin, thymoquinone, and 3, 3'-diindolylmethane combinations attenuate lung and liver cancers progression[J]. Front Pharmacol, 2022,13:936996.
[26]	SHILPA G, LAKSHMI S, JAMSHEENA V, et al. Studies on the mode of action of synthetic diindolylmethane derivatives against triple negative breast cancer cells[J]. Basic Clin Pharmacol Toxicol, 2022, 131(4):224-240. doi: 10.1111/bcpt.v131.4 URL
[27]	CHINNI S R, SARKAR F H. AKT inactivation is a key event in indole-3-carbinol-induced apoptosis in PC-3 cells[J]. Clin Cancer Res, 2002, 8(4):1228-1236. pmid: 11948137
[28]	LI Y, CHINNI S R, SARKAR F H. Selective growth regulatory and pro-apoptotic effects of dim is mediated by AKT and NF-kappab pathways in prostate cancer cells[J]. Front Biosci, 2005,10:236-243.
[29]	SINGH A A, JO S H, KIDDANE A T, et al. Indole-3-carbinol induces apoptosis in AGS cancer cells via mitochondrial pathway[J]. Chem Biol Drug Des, 2023, 101(6):1367-1381. doi: 10.1111/cbdd.v101.6 URL
[30]	SONG Q Q, LIN L P, CHEN Y L, et al. Characterization of LTr1 derived from cruciferous vegetables as a novel anti-glioma agent via inhibiting TrkA/PI3K/AKT pathway[J]. Acta Pharmacol Sin, 2023, 44(6):1262-1276. doi: 10.1038/s41401-022-01033-y
[31]	DAN H C, COOPER M J, COGSWELL P C, et al. AKT-dependent regulation of NF-{kappa}b is controlled by mTOR and raptor in association with IKK[J]. Genes Dev, 2008, 22(11):1490-1500. doi: 10.1101/gad.1662308 URL
[32]	SAFA M, TAVASOLI B, MANAFI R, et al. Indole-3-carbinol suppresses NF-κb activity and stimulates the p53 pathway in pre-B acute lymphoblastic leukemia cells[J]. Tumour Biol, 2015, 36(5):3919-3930. doi: 10.1007/s13277-014-3035-1 URL
[33]	RAHMAN K M, LI Y, SARKAR F H. Inactivation of AKT and NF-kappab play important roles during indole-3-carbinol-induced apoptosis in breast cancer cells[J]. Nutr Cancer, 2004, 48(1):84-94. doi: 10.1207/s15327914nc4801_12 pmid: 15203382
[34]	WENG J R, BAI L Y, CHIU C F, et al. The dietary phytochemical 3,3′-diindolylmethane induces G2/M arrest and apoptosis in oral squamous cell carcinoma by modulating AKT-NF-κb, MAPK, and p53 signaling[J]. Chem Biol Interact, 2012, 195(3):224-230. doi: 10.1016/j.cbi.2012.01.003 URL
[35]	TAKADA Y, ANDREEFF M, AGGARWAL B B. Indole-3-carbinol suppresses NF-κb and IκBα kinase activation, causing inhibition of expression of NF-κB-regulated antiapoptotic and metastatic gene products and enhancement of apoptosis in myeloid and leukemia cells[J]. Blood, 2005, 106(2):641-649.
[36]	WANG T T, SCHOENE N W, MILNER J A, et al. Broccoli-derived phytochemicals indole-3-carbinol and 3,3'-diindolylmethane exerts concentration-dependent pleiotropic effects on prostate cancer cells: comparison with other cancer preventive phytochemicals[J]. Mol Carcinog, 2012, 51(3):244-256. doi: 10.1002/mc.v51.3 URL
[37]	SAFE S, CHENG Y, JIN U H. The aryl hydrocarbon receptor (AhR) as a drug target for cancer chemotherapy[J]. Curr Opin Toxicol, 2017,2:24-29.
[38]	KOLLURI S K, JIN U H, SAFE S. Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target[J]. Arch Toxicol, 2017, 91(7):2497-2513. doi: 10.1007/s00204-017-1981-2 pmid: 28508231
[39]	SAITO N, KANNO Y, YAMASHITA N, et al. The differential selectivity of aryl hydrocarbon receptor (AhR) agonists towards AhR-dependent suppression of mammosphere formation and gene transcription in human breast cancer cells[J]. Biol Pharm Bull, 2021, 44(4):571-578. doi: 10.1248/bpb.b20-00961 pmid: 33790107
[40]	WANG J, JIANG Y F. Natural compounds as anticancer agents: experimental evidence[J]. World J Exp Med, 2012, 2(3):45-57. doi: 10.5493/wjem.v2.i3.45 pmid: 24520533
[41]	W WATSON G, M BEAVER L, E WILLIAMS D, et al. Phytochemicals from cruciferous vegetables, epigenetics, and prostate cancer prevention[J]. AAPS J, 2013, 15(4):951-961. doi: 10.1208/s12248-013-9504-4 pmid: 23800833
[42]	CARUSO J A, CAMPANA R, WEI C, et al. Indole-3-carbinol and its N-alkoxy derivatives preferentially target ERα-positive breast cancer cells[J]. Cell Cycle, 2014, 13(16):2587-2599. doi: 10.4161/15384101.2015.942210 pmid: 25486199
[43]	DAS S, SOMISETTY V S, ULVEN S M, et al. Resveratrol and 3,3'-diindolylmethane differentially regulate aryl hydrocarbon receptor and estrogen receptor alpha activity through multiple transcriptomic targets in MCF-7 human breast cancer cells[J]. Int J Mol Sci, 2023, 24(19).
[44]	DEGNER S C, PAPOUTSIS A J, SELMIN O, et al. Targeting of aryl hydrocarbon receptor-mediated activation of cyclooxygenase-2 expression by the indole-3-carbinol metabolite 3,3'-diindolylmethane in breast cancer cells[J]. J Nutr, 2009, 139(1):26-32. doi: 10.3945/jn.108.099259 pmid: 19056653
[45]	MARCONETT C N, SUNDAR S N, POINDEXTER K M, et al. Indole-3-carbinol triggers aryl hydrocarbon receptor-dependent estrogen receptor (ER)alpha protein degradation in breast cancer cells disrupting an ERalpha-GATA3 transcriptional cross-regulatory loop[J]. Mol Biol Cell, 2010, 21(7):1166-1177. doi: 10.1091/mbc.E09-08-0689 pmid: 20130088
[46]	MOHAMMADI S, SEYEDHOSSEINI F S, BEHNAMPOUR N, et al. Indole-3-carbinol induces G1 cell cycle arrest and apoptosis through aryl hydrocarbon receptor in THP-1 monocytic cell line[J]. J Recept Signal Transduct Res, 2017, 37(5):506-514. doi: 10.1080/10799893.2017.1360351 URL
[47]	DIAZ-DIAZ C J, RONNEKLEIV-KELLY S M, NUKAYA M, et al. The aryl hydrocarbon receptor is a repressor of inflammation-associated colorectal tumorigenesis in mouse[J]. Ann Surg, 2016, 264(3):429-436. doi: 10.1097/SLA.0000000000001874 URL
[48]	ALA M. Tryptophan metabolites modulate inflammatory bowel disease and colorectal cancer by affecting immune system[J]. Int Rev Immunol, 2021, 41(3):326-345. doi: 10.1080/08830185.2021.1954638 URL
[49]	ARELLANO-GUTIERREZ C V, QUINTAS-GRANADOS L I, CORTES H, et al. Indole-3-carbinol, a phytochemical aryl hydrocarbon receptor-ligand, induces the mrna overexpression of UBE2L3 and cell proliferation arrest[J]. Curr Issues Mol Biol, 2022, 44(5):2054-2068. doi: 10.3390/cimb44050139 URL
[50]	WANG T, PHAM Q, KIM Y. Elucidating the role of CD84 and AhR in modulation of lps-induced cytokines production by cruciferous vegetable-derived compounds indole-3-carbinol and 3,3′-diindolylmethane[J]. Int J Mol Sci, 2018, 19(2):339. doi: 10.3390/ijms19020339 URL