Molecular Targets, Anti-cancer Properties and Potency of Synthetic Indole-3-carbinol Derivatives

Author(s): Mojgan Noroozi Karimabad, Mehdi Mahmoodi, Abdolah Jafarzadeh, Ali Darekordi, Mohamad Reza Hajizadeh, Gholamhossein Hassanshahi*

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 19 , Issue 7 , 2019

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Graphical Abstract:


The indole-3-carbinol (I3C) displays anti-cancer/proliferative activities against human cancer cells. Cellular proliferation is an event associated with the progress and its continuation. This manifest is described by variation in expression and/or functions of genes that are related with cell cycle relevant proteins. The constitutive activation of several signal transduction pathways stimulates cells proliferation as well. The immediate stages in cancer development are accompanied by a fibrogenic response and the progression of the hypoxic environment is in favor of survival and proliferatory functions of cancer stem cells. A main part for prevention of in cancer cells death may manifest through altering cell metabolism. Cellular proliferation and metastasis are reported to be supported with increased generation of responsible hormones (in hormone dependent malignancies), and further promotion the angiogenesis, with epithelial to mesenchymal transition. This may be facilitated by progression of autophagy phenomenon, as well as via taking cues from neighboring stromal cells. Several signaling pathways in association with various factors specific for cellular viability, including hypoxia inducible factor 1, NF-κB, insulin-like growth factor 1 (IGF-1) receptor, Human foreskin fibroblasts (HFF-1), phosphoinositide 3 kinase/Akt, Wnt, cell cycle related protein, with androgen and estrogen receptor signaling are reported to be inhibited by I3C. These evidences, in association with bioinformatics data represent very important information for describing signaling pathways in parallel with molecular targets that may serve as markers for early diagnosis and/or critical targets for designing and development of novel therapeutic regimes alone or combined with drugs, to prevent tumor formation and further progression. In particular, I3C and DIM have been extensively investigated for their importance against numbers human cancers both in vitro and in vivo. We aimed the present manuscript, current study, to review anticancer properties and the miscellaneous mechanisms underlying the antitumorigenicity in an in-depth study for broadening the I3C treating marvel.

Keywords: Indole-3-carbinol, antitumor, cell cycle, apoptosis, cellular proliferation, insulin-like growth factor 1(IGF-1) receptor.

Gottesman, M.M. Mechanisms of cancer drug resistance. Annu. Rev. Med., 2002, 53, 615-627.
Khandany, B.K.; Hassanshahi, G.; Khorramdelazad, H.; Balali, Z.; Shamsizadeh, A.; Arababadi, M.K.; Ostadebrahimi, H.; Fatehi, A.; Rezazadeh, M.; Ahmadi, Z. Evaluation of circulating concentrations of CXCL1 (Gro-α), CXCL10 (IP-10) and CXCL12 (SDF-1) in ALL patients prior and post bone marrow transplantation. Pathol. Res. Pract., 2012, 208, 615-619.
Sheikhrezaei, Z.; Heydari, P.; Farsinezhad, A.; Fatemi, A.; Falahati-Pour, S.K.; Darakhshan, S.; Karimabad, M.N.; Darekordi, A.; Khorramdelazad, H.; Hassanshahi, G. A new indole derivative decreased SALL4 gene expression in acute Promyelocytic leukemia cell line (NB4). Iran. Biomed. J., 2018, 22, 99.
Moosavi, S.R.; Khorramdelazad, H.; Amin, M.; Fatahpoor, S.; Moogooei, M.; Karimabad, M.N.; Paghale, M.J.; Vakilian, A.; Hassanshahi, G. The SDF-1 3'A genetic variation is correlated with elevated intra-tumor tissue and circulating concentration of CXCL12 in glial tumors. J. Mol. Neurosci., 2013, 50, 298-304.
Goldie, J.H. Drug resistance in cancer: A perspective. Cancer Metastasis Rev., 2001, 20, 63-68.
Phuah, N.H.; Nagoor, N.H. Regulation of microRNAs by natural agents: New Strategies in cancer therapies. BioMed Res. Int., 2014, 804510, 17.
Karimabad, M.N.; Mahmoodi, M.; Jafarzadeh, A.; Darehkordi, A.; Hajizadeh, M.R.; Khorramdelazad, H.; Falahati-pour, S.K.; Hassanshahi, G. The novel Indole-3-formaldehyde (2-AITFEI-3-F) is involved in processes of apoptosis induction? Life Sci., 2017, 181, 31-44.
Karimabad, M.N.; Mahmoodi, M.; Jafarzadeh, A.; Darehkordi, A.; Hajizadeh, M.R.; Khorramdelazad, H.; Sayadi, A.R.; Rahmani, F.; Hassanshahi, G. Evaluating of OCT-4 and NANOG was differentially regulated by a new derivative indole in leukemia cell line. Immunol. Lett., 2017, 190, 7-14.
Steinmetz, K.A.; Potter, J.D. Vegetables, fruit, and cancer prevention: a review. J. Am. Diet. Assoc., 1996, 96, 1027-1039.
Cohen, J.H.; Kristal, A.R.; Stanford, J.L. Fruit and vegetable intakes and prostate cancer risk. J. Natl. Cancer Inst., 2000, 92, 61-68.
Higdon, J.V.; Delage, B.; Williams, D.E.; Dashwood, R.H. Cruciferous vegetables and human cancer risk: Epidemiologic evidence and mechanistic basis. Pharmacol. Res., 2007, 55, 224-236.
Minich, D.M.; Bland, J.S. A review of the clinical efficacy and safety of cruciferous vegetable phytochemicals. Nutr. Rev., 2007, 65, 259-267.
Verhoeven, D.T.; Goldbohm, R.A.; van Poppel, G.; Verhagen, H.; van den Brandt, P.A. Epidemiological studies on brassica vegetables and cancer risk. Cancer Epidemiol. Biomarkers Prev., 1996, 5, 733-748.
Weng, J.R.; Tsai, C.H.; Kulp, S.K.; Chen, C.S. Indole-3-carbinol as a chemopreventive and anti-cancer agent. Cancer Lett., 2008, 262, 153-163.
Hong, C.; Firestone, G.L.; Bjeldanes, L.F. Bcl-2 family-mediated apoptotic effects of 3,3′-diindolylmethane (DIM) in human breast cancer cells. Biochem. Pharmacol., 2002, 63, 1085-1097.
Howells, L.M.; Gallacher-Horley, B.; Houghton, C.E.; Manson, M.M.; Hudson, E.A. Indole-3-carbinol inhibits protein kinase B/Akt and induces apoptosis in the human breast tumor cell line MDA MB468 but not in the nontumorigenic HBL100 line. Mol. Cancer Ther., 2002, 1, 1161-1172.
Katdare, M.; Osborne, M.P.; Telang, N.T. Inhibition of aberrant proliferation and induction of apoptosis in pre-neoplastic human mammary epithelial cells by natural phytochemicals. Oncol. Rep., 1998, 5, 311-315.
Rahman, K.M.; Aranha, O.; Sarkar, F.H. Indole-3-carbinol (I3C) induces apoptosis in tumorigenic but not in nontumorigenic breast epithelial cells. Nutr. Cancer, 2003, 45, 101-112.
Frydoonfar, H.R.; McGrath, D.R.; Spigelman, A.D. Inhibition of proliferation of a colon cancer cell line by indole-3-carbinol. Colorectal Dis., 2002, 4, 205-207.
Hudson, E.A.; Howells, L.M.; Gallacher-Horley, B.; Fox, L.H.; Gescher, A.; Manson, M.M. Growth-inhibitory effects of the chemopreventive agent indole-3-carbinol are increased in combination with the polyamine putrescine in the SW480 colon tumour cell line. BMC Cancer, 2003, 3, 2.
Frydoonfar, H.R.; McGrath, D.R.; Spigelman, A.D. The effect of indole-3-carbinol and sulforaphane on a prostate cancer cell line. ANZ J. Surg., 2003, 73, 154-156.
Nachshon-Kedmi, M.; Yannai, S.; Haj, A.; Fares, F.A. Indole-3-carbinol and 3,3′-diindolylmethane induce apoptosis in human prostate cancer cells. Food Chem. Toxicol., 2003, 41, 745-752.
Leong, H.; Firestone, G.L.; Bjeldanes, L.F. Cytostatic effects of 3,3′-diindolylmethane in human endometrial cancer cells result from an estrogen receptor-mediated increase in transforming growth factor-alpha expression. Carcinogenesis, 2001, 22, 1809-1817.
Aggarwal, B.B.; Ichikawa, H. Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle, 2005, 4, 1201-1215.
Aggarwal, B.B.; Shishodia, S. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem. Pharmacol., 2006, 71, 1397-1421.
Kim, Y.S.; Milner, J.A. Targets for indole-3-carbinol in cancer prevention. J. Nutr. Biochem., 2005, 16, 65-73.
Rogan, E.G. The natural chemopreventive compound indole-3-carbinol: State of the science. In Vivo, 2006, 20, 221-228.
Sarkar, F.H.; Li, Y. Indole-3-carbinol and prostate cancer. J. Nutr., 2004, 134, 3493s-3498s.
Bradlow, H.L.; Michnovicz, J.; Telang, N.T.; Osborne, M.P. Effects of dietary indole-3-carbinol on estradiol metabolism and spontaneous mammary tumors in mice. Carcinogenesis, 1991, 12, 1571-1574.
Jin, L.; Qi, M.; Chen, D.Z.; Anderson, A.; Yang, G.Y.; Arbeit, J.M.; Auborn, K.J. Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice. Cancer Res., 1999, 59, 3991-3997.
Yu, Z.; Mahadevan, B.; Lohr, C.V.; Fischer, K.A.; Louderback, M.A.; Krueger, S.K.; Pereira, C.B.; Albershardt, D.J.; Baird, W.M.; Bailey, G.S.; Williams, D.E. Indole-3-carbinol in the maternal diet provides chemoprotection for the fetus against transplacental carcinogenesis by the polycyclic aromatic hydrocarbon dibenzo[a,l]pyrene. Carcinogenesis, 2006, 27, 2116-2123.
Lee, M.M.; Gomez, S.L.; Chang, J.S.; Wey, M.; Wang, R.T.; Hsing, A.W. Soy and isoflavone consumption in relation to prostate cancer risk in China. Cancer Epidemiol. Biomarkers Prev., 2003, 12, 665-668.
Naik, R.; Nixon, S.; Lopes, A.; Godfrey, K.; Hatem, M.H.; Monaghan, J.M. A randomized phase II trial of indole-3-carbinol in the treatment of vulvar intraepithelial neoplasia. Int. J. Gynecol. Cancer, 2006, 16, 786-790.
Bell, M.C.; Crowley-Nowick, P.; Bradlow, H.L.; Sepkovic, D.W.; Schmidt-Grimminger, D.; Howell, P.; Mayeaux, E.J.; Tucker, A.; Turbat-Herrera, E.A.; Mathis, J.M. Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol. Oncol., 2000, 78, 123-129.
Rosen, C.A.; Bryson, P.C. Indole-3-carbinol for recurrent respiratory papillomatosis: Long-term results. J. Voice, 2004, 18, 248-253.
Reed, G.A.; Peterson, K.S.; Smith, H.J.; Gray, J.C.; Sullivan, D.K.; Mayo, M.S.; Crowell, J.A.; Hurwitz, A. A phase I study of indole-3-carbinol in women: Tolerability and effects. Cancer Epidemiol. Biomarkers Prev., 2005, 14, 1953-1960.
Michaud, D.S.; Spiegelman, D.; Clinton, S.K.; Rimm, E.B.; Willett, W.C.; Giovannucci, E.L. Fruit and vegetable intake and incidence of bladder cancer in a male prospective cohort. J. Natl. Cancer Inst., 1999, 91, 605-613.
Johnson, I.S.; Armstrong, J.G.; Gorman, M.; Burnett, J.P., Jr The vinca alkaloids: A new class of oncolytic agents. Cancer Res., 1963, 23, 1390-1427.
Omura, S.; Iwai, Y.; Hirano, A.; Nakagawa, A.; Awaya, J.; Tsuchya, H.; Takahashi, Y.; Masuma, R. A new alkaloid AM-2282 OF Streptomyces origin. Taxonomy, fermentation, isolation and preliminary characterization. J. Antibiot. (Tokyo), 1977, 30, 275-282.
Barrios, C.H.; Liu, M.C.; Lee, S.C.; Vanlemmens, L.; Ferrero, J.M.; Tabei, T.; Pivot, X.; Iwata, H.; Aogi, K.; Lugo-Quintana, R. Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer. Breast Cancer Res. Treat., 2010, 121, 121-131.
Mina, L.; Krop, I.; Zon, R.T.; Isakoff, S.J.; Schneider, C.J.; Yu, M.; Johnson, C.; Vaughn, L.G.; Wang, Y.; Hristova-Kazmierski, M. A phase II study of oral enzastaurin in patients with metastatic breast cancer previously treated with an anthracycline and a taxane containing regimen. Invest. New Drugs, 2009, 27, 565-570.
Ahmad, A.; Biersack, B.; Li, Y.; Kong, D.; Bao, B.; Schobert, R.; Padhye, S.B.; Sarkar, F.H. Targeted regulation of PI3K/Akt/m TOR/NF-kappaB signaling by indole compounds and their derivatives: mechanistic details and biological implications for cancer therapy. Anticancer. Agents Med. Chem., 2013, 13, 1002-1013.
Reed, G.A.; Arneson, D.W.; Putnam, W.C.; Smith, H.J.; Gray, J.C.; Sullivan, D.K.; Mayo, M.S.; Crowell, J.A.; Hurwitz, A. Single-dose and multiple-dose administration of indole-3-carbinol to women: pharmacokinetics based on 3,3′-diindolylmethane. Cancer Epidemiol. Biomarkers Prev., 2006, 15, 2477-2481.
Grose, K.R.; Bjeldanes, L.F. Oligomerization of indole-3-carbinol in aqueous acid. Chem. Res. Toxicol., 1992, 5, 188-193.
Anderton, M.J.; Jukes, R.; Lamb, J.H.; Manson, M.M.; Gescher, A.; Steward, W.P.; Williams, M.L. Liquid chromatographic assay for the simultaneous determination of indole-3-carbinol and its acid condensation products in plasma. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2003, 787, 281-291.
Anderton, M.J.; Manson, M.M.; Verschoyle, R.D.; Gescher, A.; Lamb, J.H.; Farmer, P.B.; Steward, W.P.; Williams, M.L. Pharmacokinetics and tissue disposition of indole-3-carbinol and its acid condensation products after oral administration to mice. Clin. Cancer Res., 2004, 10, 5233-5241.
De Kruif, C.A.; Marsman, J.W.; Venekamp, J.C.; Falke, H.E.; Noordhoek, J.; Blaauboer, B.J.; Wortelboer, H.M. Structure elucidation of acid reaction products of indole-3-carbinol: Detection in vivo and enzyme induction in vitro. Chem. Biol. Interact., 1991, 80, 303-315.
Stresser, D.M.; Williams, D.E.; Griffin, D.A.; Bailey, G.S. Mechanisms of tumor modulation by indole-3-carbinol. Disposition and excretion in male Fischer 344 rats. Drug Metab. Dispos., 1995, 23, 965-975.
Abdelrahim, M.; Newman, K.; Vanderlaag, K.; Samudio, I.; Safe, S. 3,3′-diindolylmethane (DIM) and its derivatives induce apoptosis in pancreatic cancer cells through endoplasmic reticulum stress-dependent upregulation of DR5. Carcinogenesis, 2006, 27, 717-728.
Rahman, K.W.; Li, Y.; Wang, Z.; Sarkar, S.H.; Sarkar, F.H. Gene expression profiling revealed survivin as a target of 3,3′-diindolylmethane-induced cell growth inhibition and apoptosis in breast cancer cells. Cancer Res., 2006, 66, 4952-4960.
Herrmann, S.; Seidelin, M.; Bisgaard, H.C.; Vang, O. Indolo[3,2-b]carbazole inhibits gap junctional intercellular communication in rat primary hepatocytes and acts as a potential tumor promoter. Carcinogenesis, 2002, 23, 1861-1868.
Liu, H.; Wormke, M.; Safe, S.H.; Bjeldanes, L.F. Indolo[3,2-b]carbazole: a dietary-derived factor that exhibits both antiestrogenic and estrogenic activity. J. Natl. Cancer Inst., 1994, 86, 1758-1765.
Weng, J.R.; Omar, H.A.; Kulp, S.K.; Chen, C.S. Pharmacological exploitation of indole-3-carbinol to develop potent antitumor agents. Mini Rev. Med. Chem., 2010, 10, 398-404.
Brandi, G.; Paiardini, M.; Cervasi, B.; 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, 63, 4028-4036.
Moore, R.W.; Fritz, W.A.; Schneider, A.J.; Lin, T.M.; Branam, A.M.; Safe, S.; Peterson, R.E. 2,3,7,8-Tetrachlorodibenzo-p-dioxin has both pro-carcinogenic and anti-carcinogenic effects on neuroendocrine prostate carcinoma formation in TRAMP mice. Toxicol. Appl. Pharmacol., 2016, 305, 242-249.
Poindexter, K.M.; Matthew, S.; Aronchik, I.; Firestone, G.L. Cooperative antiproliferative signaling by aspirin and indole-3-carbinol targets microphthalmia-associated transcription factor gene expression and promoter activity in human melanoma cells. Cell Biol. Toxicol., 2016, 32, 103-119.
Lawrie, T.A.; Nordin, A.; Chakrabarti, M.; Bryant, A.; Kaushik, S.; Pepas, L. Medical and surgical interventions for the treatment of usual-type vulval intraepithelial neoplasia. Cochrane Database Syst. Rev., 2016, 1, Cd011837.
Adwas, A.A.; Elkhoely, A.A.; Kabel, A.M.; Abdel-Rahman, M.N.; Eissa, A.A. Anti-cancer and cardioprotective effects of indol-3-carbinol in doxorubicin-treated mice. J. Infect. Chemother., 2016, 22, 36-43.
Chinni, S.R.; Sarkar, F.H. Akt inactivation is a key event in indole-3-carbinol-induced apoptosis in PC-3 cells. Clin. Cancer Res., 2002, 8, 1228-1236.
Rahman, K.W.; Sarkar, F.H. Inhibition of nuclear translocation of nuclear factor-kappaB contributes to 3,3′-diindolylmethane-induced apoptosis in breast cancer cells. Cancer Res., 2005, 65, 364-371.
Bellacosa, A.; Kumar, C.C.; Di Cristofano, A.; Testa, J.R. Activation of AKT kinases in cancer: Implications for therapeutic targeting. Adv. Cancer Res., 2005, 94, 29-86.
Yoeli-Lerner, M.; Toker, A. Akt/PKB signaling in cancer: A function in cell motility and invasion. Cell Cycle, 2006, 5, 603-605.
Aggarwal, B.B. Nuclear factor-kappaB: The enemy within. Cancer Cell, 2004, 6, 203-208.
Weng, J.R.; Tsai, C.H.; Kulp, S.K.; Wang, D.; Lin, C.H.; Yang, H.C.; Ma, Y.; Sargeant, A.; Chiu, C.F.; Tsai, M.H.; Chen, C.S. A potent indole-3-carbinol derived antitumor agent with pleiotropic effects on multiple signaling pathways in prostate cancer cells. Cancer Res., 2007, 67, 7815-7824.
Lian, J.P.; Word, B.; Taylor, S.; Hammons, G.J.; Lyn-Cook, B.D. Modulation of the constitutive activated STAT3 transcription factor in pancreatic cancer prevention: Effects of indole-3-carbinol (I3C) and genistein. Anticancer Res., 2004, 24, 133-137.
Hwang, J.W.; Jung, J.W.; Lee, Y.S.; Kang, K.S. Indole-3-carbinol prevents H(2)O(2)-induced inhibition of gap junctional intercellular communication by inactivation of PKB/Akt. J. Vet. Med. Sci., 2008, 70, 1057-1063.
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. Front. Biosci., 2005, 10, 236-243.
Staudt, L.M. Oncogenic activation of NF-kappaB. Cold Spring Harb. Perspect, 2010, 2, a000109.
Garikapaty, V.P.; Ashok, B.T.; Tadi, K.; Mittelman, A.; Tiwari, R.K. Synthetic dimer of indole-3-carbinol: Second generation diet derived anti-cancer agent in hormone sensitive prostate cancer. Prostate, 2006, 66, 453-462.
Garikapaty, V.P.; Ashok, B.T.; Tadi, K.; Mittelman, A.; Tiwari, R.K. 3,3′-Diindolylmethane downregulates pro-survival pathway in hormone independent prostate cancer. Biochem. Biophys. Res. Commun., 2006, 340, 718-725.
Falasca, M.; Selvaggi, F.; Buus, R.; Sulpizio, S.; Edling, C.E. Targeting phosphoinositide 3-kinase pathways in pancreatic cancer--from molecular signalling to clinical trials. Anticancer. Agents Med. Chem., 2011, 11, 455-463.
Karin, M. Nuclear factor-kappaB in cancer development and progression. Nature, 2006, 441, 431-436.
Luqman, S.; Pezzuto, J.M. NFkappaB: A promising target for natural products in cancer chemoprevention. Phytother. Res., 2010, 24, 949-963.
Karin, M.; Cao, Y.; Greten, F.R.; Li, Z.W. NF-kappaB in cancer: from innocent bystander to major culprit. Nat. Rev. Cancer, 2002, 2, 301-310.
Li, Y.; Li, X.; Sarkar, F.H. Gene expression profiles of I3C- and DIM-treated PC3 human prostate cancer cells determined by cDNA microarray analysis. J. Nutr., 2003, 133, 1011-1019.
Carter, T.H.; Liu, K.; Ralph, W., Jr; Chen, D.; Qi, M.; Fan, S.; Yuan, F.; Rosen, E.M.; Auborn, K.J. Diindolylmethane alters gene expression in human keratinocytes in vitro. J. Nutr., 2002, 132, 3314-3324.
Sun, S.; Han, J.; Ralph, W.M., Jr; Chandrasekaran, A.; Liu, K.; Auborn, K.J.; Carter, T.H. Endoplasmic reticulum stress as a correlate of cytotoxicity in human tumor cells exposed to diindolylmethane in vitro. Cell Stress Chaperones, 2004, 9, 76-87.
Meng, Q.; Qi, M.; Chen, D.Z.; Yuan, R.; Goldberg, I.D.; Rosen, E.M.; Auborn, K.; Fan, S. Suppression of breast cancer invasion and migration by indole-3-carbinol: Associated with up-regulation of BRCA1 and E-cadherin/catenin complexes. J. Mol. Med. (Berl.), 2000, 78, 155-165.
Chen, Y.H.; Yang, D. Differential effects of vegetable-derived indoles on the induction of quinone reductase in hepatoma cells. J. Nutr. Sci. Vitaminol. (Tokyo), 2002, 48, 477-482.
Lee, I.J.; Han, F.; Baek, J.; Hisatsune, A.; Kim, K.C. Inhibition of MUC1 expression by indole-3-carbinol. Int. J. Cancer, 2004, 109, 810-816.
Lee, S.H.; Kim, J.S.; Yamaguchi, K.; Eling, T.E.; Baek, S.J. Indole-3-carbinol and 3,3′-diindolylmethane induce expression of NAG-1 in a p53-independent manner. Biochem. Biophys. Res. Commun., 2005, 328, 63-69.
Chatterji, U.; Riby, J.E.; Taniguchi, T.; Bjeldanes, E.L.; Bjeldanes, L.F.; Firestone, G.L. Indole-3-carbinol stimulates transcription of the interferon gamma receptor 1 gene and augments interferon responsiveness in human breast cancer cells. Carcinogenesis, 2004, 25, 1119-1128.
Tutt, A.; Ashworth, A. The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. Trends Mol. Med., 2002, 8, 571-576.
Arora, A.; Seth, K.; Kalra, N.; Shukla, Y. Modulation of P-glycoprotein-mediated multidrug resistance in K562 leukemic cells by indole-3-carbinol. Toxicol. Appl. Pharmacol., 2005, 202, 237-243.
Arora, A.; Shukla, Y. Modulation of vinca-alkaloid induced P-glycoprotein expression by indole-3-carbinol. Cancer Lett., 2003, 189, 167-173.
Christensen, J.G.; LeBlanc, G.A. Reversal of multidrug resistance in vivo by dietary administration of the phytochemical indole-3-carbinol. Cancer Res., 1996, 56, 574-581.
Chinni, S.R.; Li, Y.; Upadhyay, S.; Koppolu, P.K.; Sarkar, F.H. Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells. Oncogene, 2001, 20, 2927-2936.
Matsuzaki, Y.; Koyama, M.; Hitomi, T.; Kawanaka, M.; Sakai, T. Indole-3-carbinol activates the cyclin-dependent kinase inhibitor p15(INK4b) gene. FEBS Lett., 2004, 576, 137-140.
Takada, Y.; Andreeff, M.; Aggarwal, B.B. Indole-3-carbinol suppresses NF-kappaB and IkappaBalpha kinase activation, causing inhibition of expression of NF-kappaB-regulated antiapoptotic and metastatic gene products and enhancement of apoptosis in myeloid and leukemia cells. Blood, 2005, 106, 641-649.
Ge, X.; Fares, F.A.; Yannai, S. Induction of apoptosis in MCF-7 cells by indole-3-carbinol is independent of p53 and bax. Anticancer Res., 1999, 19, 3199-3203.
Ashok, B.T.; Chen, Y.G.; Liu, X.; Garikapaty, V.P.; Seplowitz, R.; Tschorn, J.; Roy, K.; Mittelman, A.; Tiwari, R.K. Multiple molecular targets of indole-3-carbinol, a chemopreventive anti-estrogen in breast cancer. Eur. J. Cancer Prev., 2002, 11(Suppl. 2), S86-S93.
Meng, Q.; Yuan, F.; Goldberg, I.D.; Rosen, E.M.; Auborn, K.; Fan, S. Indole-3-carbinol is a negative regulator of estrogen receptor-alpha signaling in human tumor cells. J. Nutr., 2000, 30, 2927-2931.
Fan, S.; Meng, Q.; Auborn, K.; Carter, T.; Rosen, E.M. BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells. Br. J. Cancer, 2006, 94, 407-426.
Grubbs, C.J.; Steele, V.E.; Casebolt, T.; Juliana, M.M.; Eto, I.; Whitaker, L.M.; Dragnev, K.H.; Kelloff, G.J.; Lubet, R.L. Chemoprevention of chemically-induced mammary carcinogenesis by indole-3-carbinol. Anticancer Res., 1995, 15, 709-716.
Michnovicz, J.J.; Bradlow, H.L. Induction of estradiol metabolism by dietary indole-3-carbinol in humans. J. Natl. Cancer Inst., 1990, 82, 947-949.
Jellinck, P.H.; Michnovicz, J.J.; Bradlow, H.L. Influence of indole-3-carbinol on the hepatic microsomal formation of catechol estrogens. Steroids, 1991, 56, 446-450.
Hsu, J.C.; Zhang, J.; Dev, A.; Wing, A.; Bjeldanes, L.F.; Firestone, G.L. Indole-3-carbinol inhibition of androgen receptor expression and downregulation of androgen responsiveness in human prostate cancer cells. Carcinogenesis, 2005, 26, 1896-1904.
Traber, P.G.; Chianale, J.; Florence, R.; Kim, K.; Wojcik, E.; Gumucio, J.J. Expression of cytochrome P450b and P450e genes in small intestinal mucosa of rats following treatment with phenobarbital, polyhalogenated biphenyls, and organochlorine pesticides. J. Biol. Chem., 1988, 263, 9449-9455.
Chen, I.; Safe, S.; Bjeldanes, L. Indole-3-carbinol and diindolylmethane as aryl hydrocarbon (Ah) receptor agonists and antagonists in T47D human breast cancer cells. Biochem. Pharmacol., 1996, 51, 1069-1076.
Li, Y.; Kong, D.; Ahmad, A.; Bao, B.; Sarkar, F.H. Antioxidant function of isoflavone and 3,3′-diindolylmethane: Are they important for cancer prevention and therapy? Antioxid. Redox Signal., 2013, 19, 139-150.
Safe, S.; Papineni, S.; Chintharlapalli, S. Cancer chemotherapy with indole-3-carbinol, bis(3′-indolyl)methane and synthetic analogs. Cancer Lett., 2008, 269, 326-338.
Mei, S.; Ho, A.D.; Mahlknecht, U. Role of histone deacetylase inhibitors in the treatment of cancer (Review). Int. J. Oncol., 2004, 25, 1509-1519.
McNaughton, S.A.; Marks, G.C. Development of a food composition database for the estimation of dietary intakes of glucosinolates, the biologically active constituents of cruciferous vegetables. Br. J. Nutr., 2003, 90, 687-697.
Myzak, M.C.; Karplus, P.A.; Chung, F.L.; Dashwood, R.H. A novel mechanism of chemoprotection by sulforaphane: Inhibition of histone deacetylase. Cancer Res., 2004, 64, 5767-5774.
Lea, M.A.; Rasheed, M.; Randolph, V.M.; Khan, F.; Shareef, A.; desBordes, C. Induction of histone acetylation and inhibition of growth of mouse erythroleukemia cells by S-allylmercaptocysteine. Nutr. Cancer, 2002, 43, 90-102.
Myzak, M.C.; Hardin, K.; Wang, R.; Dashwood, R.H.; Ho, E. Sulforaphane inhibits histone deacetylase activity in BPH-1, LnCaP and PC-3 prostate epithelial cells. Carcinogenesis, 2006, 27, 811-819.
Ghoshal, K.; Li, X.; Datta, J.; Bai, S.; Pogribny, I.; Pogribny, M.; Huang, Y.; Young, D.; Jacob, S.T. A folate- and methyl-deficient diet alters the expression of DNA methyltransferases and methyl CpG binding proteins involved in epigenetic gene silencing in livers of F344 rats. J. Nutr., 2006, 136, 1522-1527.
Dolinoy, D.C.; Weidman, J.R.; Waterland, R.A.; Jirtle, R.L. Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environ. Health Perspect., 2006, 114, 567-572.
Kim, Y.H.; Kwon, H.S.; Kim, D.H.; Shin, E.K.; Kang, Y.H.; Park, J.H.; Shin, H.K.; Kim, J.K. 3,3′-diindolylmethane attenuates colonic inflammation and tumorigenesis in mice. Inflamm. Bowel Dis., 2009, 15, 1164-1173.
Moiseeva, E.P.; Almeida, G.M.; Jones, G.D.; Manson, M.M. Extended treatment with physiologic concentrations of dietary phytochemicals results in altered gene expression, reduced growth, and apoptosis of cancer cells. Mol. Cancer Ther., 2007, 6, 3071-3079.
Sarkar, F.H.; Rahman, K.M.; Li, Y. Bax translocation to mitochondria is an important event in inducing apoptotic cell death by indole-3-carbinol (I3C) treatment of breast cancer cells. J. Nutr., 2003, 133, 2434s-2439s.
Zhang, J.; Hsu, B.A.J.; Kinseth, B.A.M.; Bjeldanes, L.F.; Firestone, G.L. Indole-3-carbinol induces a G1 cell cycle arrest and inhibits prostate-specific antigen production in human LNCaP prostate carcinoma cells. Cancer, 2003, 98, 2511-2520.
Ali, S.; Banerjee, S.; Ahmad, A.; El-Rayes, B.F.; Philip, P.A.; Sarkar, F.H. Apoptosis-inducing effect of erlotinib is potentiated by 3,3′-diindolylmethane in vitro and in vivo using an orthotopic model of pancreatic cancer. Mol. Cancer Ther., 2008, 7, 1708-1719.
Ali, S.; Varghese, L.; Pereira, L.; Tulunay-Ugur, O.E.; Kucuk, O.; Carey, T.E.; Wolf, G.T.; Sarkar, F.H. Sensitization of squamous cell carcinoma to cisplatin induced killing by natural agents. Cancer Lett., 2009, 278, 201-209.
Donald, S.; Verschoyle, R.D.; Greaves, P.; Colombo, T.; Zucchetti, M.; Falcioni, C.; Zaffaroni, M.; D’Incalci, M.; Manson, M.M.; Jimeno, J. Dietary agent indole-3-carbinol protects female rats against the hepatotoxicity of the antitumor drug ET-743 (trabectidin) without compromising efficacy in a rat mammary carcinoma. Int. J. Cancer, 2004, 111, 961-967.
Singh-Gupta, V.; Banerjee, S.; Yunker, C.K.; Rakowski, J.T.; Joiner, M.C.; Konski, A.A.; Sarkar, F.H.; Hillman, G.G. B-DIM impairs radiation-induced survival pathways independently of androgen receptor expression and augments radiation efficacy in prostate cancer. Cancer Lett., 2012, 318, 86-92.
Verhoeven, D.T.; Verhagen, H.; Goldbohm, R.A.; van den Brandt, P.A.; van Poppel, G. A review of mechanisms underlying anticarcinogenicity by brassica vegetables. Chem. Biol. Interact., 1997, 103, 79-129.
Kojima, T.; Tanaka, T.; Mori, H. Chemoprevention of spontaneous endometrial cancer in female Donryu rats by dietary indole-3-carbinol. Cancer Res., 1994, 54, 1446-1449.
Manson, M.M.; Hudson, E.A.; Ball, H.W.; Barrett, M.C.; Clark, H.L.; Judah, D.J.; Verschoyle, R.D.; Neal, G.E. Chemoprevention of aflatoxin B1-induced carcinogenesis by indole-3-carbinol in rat liver--predicting the outcome using early biomarkers. Carcinogenesis, 1998, 19, 1829-1836.
Stresser, D.M.; Bailey, G.S.; Williams, D.E. Indole-3-carbinol and beta-naphthoflavone induction of aflatoxin B1 metabolism and cytochromes P-450 associated with bioactivation and detoxication of aflatoxin B1 in the rat. Drug Metab. Dispos., 1994, 22, 383-391.
Bradfield, C.A.; Bjeldanes, L.F. Effect of dietary indole-3-carbinol on intestinal and hepatic monooxygenase, glutathione S-transferase and epoxide hydrolase activities in the rat. Food Chem. Toxicol., 1984, 22, 977-982.
Kassie, F.; Anderson, L.B.; Scherber, R.; Yu, N.; Lahti, D.; Upadhyaya, P.; Hecht, S.S. Indole-3-carbinol inhibits 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone plus benzo(a)pyrene-induced lung tumorigenesis in A/J mice and modulates carcinogen-induced alterations in protein levels. Cancer Res., 2007, 67, 6502-6511.
Oganesian, A.; Hendricks, J.D.; Pereira, C.B.; Orner, G.A.; Bailey, G.S.; Williams, D.E. Potency of dietary indole-3-carbinol as a promoter of aflatoxin B1-initiated hepatocarcinogenesis: results from a 9000 animal tumor study. Carcinogenesis, 1999, 20, 453-458.
Doppalapudi, R.S.; Riccio, E.S.; Rausch, L.L.; Shimon, J.A.; Lee, P.S.; Mortelmans, K.E.; Kapetanovic, I.M.; Crowell, J.A.; Mirsalis, J.C. Evaluation of chemopreventive agents for genotoxic activity. Mutat. Res., 2007, 629, 148-160.
Chang, X.; Tou, J.C.; Hong, C.; Kim, H.A.; Riby, J.E.; Firestone, G.L.; Bjeldanes, L.F. 3,3′-Diindolylmethane inhibits angiogenesis and the growth of transplantable human breast carcinoma in athymic mice. Carcinogenesis, 2005, 26, 771-778.
Kong, D.; Banerjee, S.; Huang, W.; Li, Y.; Wang, Z.; Kim, H.R.; Sarkar, F.H. Mammalian target of rapamycin repression by 3,3′-diindolylmethane inhibits invasion and angiogenesis in platelet-derived growth factor-D-overexpressing PC3 cells. Cancer Res., 2008, 68, 1927-1934.
Kong, D.; Li, Y.; Wang, Z.; Banerjee, S.; Sarkar, F.H. Inhibition of angiogenesis and invasion by 3,3′-diindolylmethane is mediated by the nuclear factor-kappaB downstream target genes MMP-9 and uPA that regulated bioavailability of vascular endothelial growth factor in prostate cancer. Cancer Res., 2007, 67, 3310-3319.
Nachshon-Kedmi, M.; Fares, F.A.; Yannai, S. Therapeutic activity of 3,3′-diindolylmethane on prostate cancer in an in vivo model. Prostate, 2004, 61, 153-160.
Sarkar, F.H.; Li, Y. Harnessing the fruits of nature for the development of multi-targeted cancer therapeutics. Cancer Treat. Rev., 2009, 35, 597-607.
Reed, G.A.; Sunega, J.M.; Sullivan, D.K.; Gray, J.C.; Mayo, M.S.; Crowell, J.A.; Hurwitz, A. Single-dose pharmacokinetics and tolerability of absorption-enhanced 3,3′-diindolylmethane in healthy subjects. Cancer Epidemiol. Biomarkers Prev., 2008, 17, 2619-2624.
Bhuiyan, M.M.; Li, Y.; Banerjee, S.; Ahmed, F.; Wang, Z.; Ali, S.; Sarkar, F.H. Down-regulation of androgen receptor by 3,3′-diindolylmethane contributes to inhibition of cell proliferation and induction of apoptosis in both hormone-sensitive LNCaP and insensitive C4-2B prostate cancer cells. Cancer Res., 2006, 66, 10064-10072.
Li, Y.; Wang, Z.; Kong, D.; Murthy, S.; Dou, Q.P.; Sheng, S.; Reddy, G.P.; Sarkar, F.H. Regulation of FOXO3a/beta-catenin/ GSK-3beta signaling by 3,3′-diindolylmethane contributes to inhibition of cell proliferation and induction of apoptosis in prostate cancer cells. J. Biol. Chem., 2007, 282, 21542-21550.
Heath, E.I.; Heilbrun, L.K.; Li, J.; Vaishampayan, U.; Harper, F.; Pemberton, P.; Sarkar, F.H. 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, 402-411.
Song, J.M.; Qian, X.; Molla, K.; Teferi, F.; Upadhyaya, P. G, O.S.; Luo, X.; Kassie, F. Combinations of indole-3-carbinol and silibinin suppress inflammation-driven mouse lung tumorigenesis by modulating critical cell cycle regulators. Carcinogenesis, 2015, 36, 666-675.
Li, W.X.; Chen, L.P.; Sun, M.Y.; Li, J.T.; Liu, H.Z.; Zhu, W. 3′3-Diindolylmethane inhibits migration, invasion and metastasis of hepatocellular carcinoma by suppressing FAK signaling. Oncotarget, 2015, 6, 23776-23792.
Song, J.M.; Kirtane, A.R.; Upadhyaya, P.; Qian, X.; Balbo, S.; Teferi, F.; Panyam, J.; Kassie, F. Intranasal delivery of liposomal indole-3-carbinol improves its pulmonary bioavailability. Int. J. Pharm., 2014, 477, 96-101.
Lee, S.H.; Min, K.W.; Zhang, X.; Baek, S.J. 3,3′-diindolylmethane induces activating transcription factor 3 (ATF3) via ATF4 in human colorectal cancer cells. J. Nutr. Biochem., 2013, 24, 664-671.
Suzui, M.; Inamine, M.; Kaneshiro, T.; Morioka, T.; Yoshimi, N.; Suzuki, R.; Kohno, H.; Tanaka, T. Indole-3-carbinol inhibits the growth of human colon carcinoma cells but enhances the tumor multiplicity and volume of azoxymethane-induced rat colon carcinogenesis. Int. J. Oncol., 2005, 27, 1391-1399.
Pappa, G.; Strathmann, J.; Lowinger, M.; Bartsch, H.; Gerhauser, C. Quantitative combination effects between sulforaphane and 3,3′-diindolylmethane on proliferation of human colon cancer cells in vitro. Carcinogenesis, 2007, 28, 1471-1477.
Wang, S.Q.; Cheng, L.S.; Liu, Y.; Wang, J.Y.; Jiang, W. Indole-3-Carbinol (I3C) and its Major derivatives: Their pharmacokinetics and important roles in hepatic protection. Curr. Drug Metab., 2016, 17, 401-409.
Wang, X.; He, H.; Lu, Y.; Ren, W.; Teng, K.Y.; Chiang, C.L.; Yang, Z.; Yu, B.; Hsu, S.; Jacob, S.T. Indole-3-carbinol inhibits tumorigenicity of hepatocellular carcinoma cells via suppression of microRNA-21 and upregulation of phosphatase and tensin homolog. Biochim. Biophys, 2015, 1853, 244-253.
De Santi, M.; Galluzzi, L.; Lucarini, S.; Paoletti, M.F.; Fraternale, A.; Duranti, A.; De Marco, C.; Fanelli, M.; Zaffaroni, N.; Brandi, G. The indole-3-carbinol cyclic tetrameric derivative CTet inhibits cell proliferation via overexpression of p21/CDKN1A in both estrogen receptor-positive and triple-negative breast cancer cell lines. Breast Cancer Res., 2011, 13, R33.
Caruso, J.A.; Campana, R.; Wei, C.; Su, C.H.; Hanks, A.M.; Bornmann, W.G.; Keyomarsi, K. Indole-3-carbinol and its N-alkoxy derivatives preferentially target ERalpha-positive breast cancer cells. Cell Cycle, 2014, 13, 2587-2599.
Tin, A.S.; Park, A.H.; Sundar, S.N.; Firestone, G.L. Essential role of the cancer stem/progenitor cell marker nucleostemin for indole-3-carbinol anti-proliferative responsiveness in human breast cancer cells. BMC Biol., 2014, 12, 72.
Cevatemre, B.; Ari, F.; Sarimahmut, M.; Oral, A.Y.; Dere, E.; Kacar, O.; Adiguzel, Z.; Acilan, C.; Ulukaya, E. Combination of fenretinide and indole-3-carbinol results in synergistic cytotoxic activity inducing apoptosis against human breast cancer cells in vitro. Anticancer Drugs, 2013, 24, 577-586.
Bai, L.Y.; Weng, J.R.; Chiu, C.F.; Wu, C.Y.; Yeh, S.P.; Sargeant, A.M.; Lin, P.H.; Liao, Y.M. OSU-A9, an indole-3-carbinol derivative, induces cytotoxicity in acute myeloid leukemia through reactive oxygen species-mediated apoptosis. Biochem. Pharmacol., 2013, 86, 1430-1440.
Perez-Chacon, G.; Martinez-Laperche, C.; Rebolleda, N.; Somovilla-Crespo, B.; Munoz-Calleja, C.; Buno, I.; Zapata, J.M. Indole-3-carbinol synergizes with and restores fludarabine sensitivity in chronic lymphocytic leukemia cells irrespective of p53 activity and treatment resistances. Clin. Cancer Res., 2016, 22, 134-145.
Watson, W.G. 1.; Beaver, M.L.; Williams, E.D.; Dashwood, H.R.; Ho, E. Phytochemicals from cruciferous vegetables, epigenetics, and prostate cancer prevention. AAPS J., 2013, 15, 951-961.
Kim, E-K.; Kim, Y.S.; Milner, J.A.; Wang, T.T. Indole-3-carbinol and 3′, 3′-diindolylmethane modulate androgen’s effect on CC chemokine ligand 2 and monocyte attraction to prostate cancer cells. Cancer Preven. Res, 2013, 419, 2012.
Chen, D.; Banerjee, S.; Cui, Q.C.; Kong, D.; Sarkar, F.H.; Dou, Q.P. Activation of AMP-activated protein kinase by 3, 3′-diindolylmethane (DIM) is associated with human prostate cancer cell death in vitro and in vivo. PLoS One, 2012, 7, e47186.
Beaver, L.M.; Yu, T-W.; Sokolowski, E.I.; Williams, D.E.; Dashwood, R.H.; Ho, E. 3, 3′-Diindolylmethane, but not indole-3-carbinol, inhibits histone deacetylase activity in prostate cancer cells. Toxicol. Appl. Pharmacol., 2012, 263, 345-351.

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Year: 2019
Published on: 28 March, 2019
Page: [540 - 554]
Pages: 15
DOI: 10.2174/1389557518666181116120145
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