Indole 3-Carbinol

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  • 1. Indole-3-CarbinolProperties, Targets, Required Animal DataDr. Bhaswat S. Chakraborty1

2. Indole-3-carbinol (I3C) belongs to dietary polyphenols which include flavonoids, stillbenes, lignas, and phenolic acids I3C is produced by the breakdown of the glucosinolate viz. glucobrassicin found at relatively high levels in cruciferous vegetables, e.g., broccoli, cabbage, cauliflower, brussels sprouts, collard greens and kale cruciferous vegetables differ from other classes of vegetables in that they are rich sources of sulfur-containing compounds (glucosinolates) cruciferous vegetables are associated with lower risk of several types of cancer (epidemiologic evidence) 2 3. I3C: Off-white powder; mixes with water Average Molecular Weight 147.1739 Melting Point 90 C Water Solubility 3.75 g/L pKa ? (can act as both an electron donor & acceptor) pH (1% solution) ? storage temp. 2-8C Oral formulations can be made 3 4. Hydrolysis of glucobrassicin by myrosinase at neutral pH results in an unstable indole isothiocyanate that degrades to form I3C and a thiocyanate ion At acidic pH (stomach), I3C condenses to dimers (3,3'-diindolylmethane, DIM) & trimers (Cyclononal tri-indole, CT) When cruciferous vegetables are cooked (inactivating myrosinase), glucobrassicin hydrolysis by intestinal bacteria still results in some I3C formation, whereas DIM & CT do not form in alkaline pH of intestine 4 5. QSAR & CoMFA At least one 3D-QSAR Comparative Molecular Field Analysis (CoMFA) study of 14 DIM derivatives is reported The CoMFA model derived from DIM analogues proved a good predictive ability Some newly designed compounds exhibited 3-fold more potent radical scavenging activity than reference substance Vitamin E in DPPH model expressed by IC50 values The primary antitumor screening essay showed that some DIM derivatives designed exhibited the inhibitory activities to some tumor cell growth at relatively high concentration, and DIM was the most effective among them Relaiable 3D-QSAR model can be developed for radical scavenging activities and anticancer assays in vitro.Benabadji SH et al., Acta Pharmacol Sin 2004; 25: 666-6715 6. PK of I3C Very little data Gastric acid converts I3C to active metabolites DIM and indolylcarbazole, which are further metabolized in the liver most metabolites are excreted through the feces Conversion from I3C into DIM not only requires a precise acidity, it requires time. This conversion may proceed slowly, requiring more time than most foods typically spend in the intestinal tract Following an oral dose of I3C in humans, only DIM and no I3C was found circulating in the bloodstream of human subjects Over 90% of an oral dose of I3C is converted into non-DIM condensation products of uncertain structure, uptake and activity I3C induces CYP 1A2 and can reduce serum concentration of drugs metabolized by this enzymeArneson, DW et al., Proceedings of the American Association for Cancer Research, 1999 Mar; (40): #2833 Cover CM, et al. Cancer Res 1999; 59:1244-51 Yoshida M et al., Carcinogenesis. 2004 Nov;25(11):2257-646 7. Anti-Inflammatory Properties and Mechanisms7 8. Several dietary polyphenol compounds (e.g. resveratrol, genistein, catechin, and indole-3-carbinol) have been studied for inflammation and cancer. The potential molecular mechanisms of their antiinflammatory activities have also been suggested to include inhibition of enzymes related to inflammation: cyclooxygenase and lipoxygenase PPAR NOS NF-B NAG-1 Mainly AA-Dependent pathway AA-Independent pathway Baek SJ et al. Carcinogenesis, 2004;25:2425-32. Baek SJ et al. Carcinogenesis, 2002;23:425-34. Lee SH, et al. Biochem Biophys Res Commun, 2005;328:63-9. Wilson LC et al. Int J Cancer 2003;105:747-53. 8 9. AA- Dependent Mechanisms Aspirin and other NSAIDs block COX-1 and COX-2 The role of COX inhibition by I3C is not very clear but all NF-B-regulated gene products including COX-2 are down-regulated by I3C however, some dietary polyphenols, such as galangin and luteolin, and curcumin inhibit AA peroxidation Flavonols, including kaempferol, quercetin, morin and myricetin, were found to be 5LOX inhibitors. Hamamelitannin and the galloylated proanthocyanidins were found to be the most potent inhibitors of 5-LOX. In contrast, there are few reports regarding 12-LOX inhibition. Using bovine PMNs and 12-LOX from bovine platelets, kuwanson C and quercetin potently inhibit 12-LOX activity Again, LOX inhibition by I3C is not very clear but all NF-B-regulated gene products including LOX are down-regulated by I3C and DIM Both COX and LOX are blocked by curcumin Quercetin was found to be an effective inhibitor of PLA2 in human38 and rabbit39 leukocytes. Quercetagetin, kaempferol-3-O-galactoside, and scutellarein inhibited human recombinant synovial PLA2.Yoon J-H & Baek SJ, Yonsei Medical Journal 2005, 46, 585 - 5969 10. 10 11. AA- Independent Mechanisms PPARs (nuclear hormone receptors) regulate many inflammatory cytokines at the transcriptional level, either enhancing or inhibiting inflammation process Genistein increased the expression of lipid catabolism genes (this effect is not estrogen receptordependent, but PPAR-dependent). EGCG also binds to PPAR. Amentoflavone up-regulates PPAR expression in A549 human lung epithelial cells. Few studies regarded polyphenols as PPAR ligands, but it is probable that polyphenols may also affect PPAR protein expression, which results in the activation of the PPAR pathway Effect of I3C on PPARs not reported Nitric oxide synthase (NOS) endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS): many polyphenols, including 6-gingerol,64 EGCG,65 resveratrol, indole-3-carbinol, and oroxylin A, inhibit NOS expression in LPS-induced RAW264.7 cells (these effects are probably mediated by NF-B) Nuclear transcription factor B (NF-B): Quercetin was reported to suppress TNF- induced expression of IL-8 and monocyte chemoattractant protein (MCP-1) due to its ability to inhibit the activation of NF-B. Quercetin also inhibited the NF-B pathway without any modification of c-Jun N- terminal kinase activity both in vivo & in vitro Recently, it has been reported that I3C inhibits NF-B and NF-B-regulated gene expression. NAG-1 (NSAID activated gene-1): I3C and other polyphenols induce NAG-1 expression, except (-) -epicatechin (EC) and (-)-epigallocatechin (EGC), indicating the structure-specific expression of NAG-1 induction Yoon J-H & Baek SJ, Yonsei Medical Journal 2005, 46, 585 - 59611 12. Anticancer Properties & Mechanisms12 13. Anticancer Properties I3C & DIM are good candidates for cancer prevention. Several studies demonstrate that they can cause cell cycle arrest and apoptosis in cancer cell lines have antiangiogenic activity inhibit tobacco smoke-induced lung adenocarcinoma in mice I3C enhances efficacy of gemcitabine and acts synergistically with bortezomib in vitro.Clinical trial data show that I3C is effective in treatment of precancerous cervical dysplasia and vulvar intraepithelial neoplasia In premenopausal women, a supplement containing I3C and 7-hydroxymatairesinol significantly increased the urinary 2:16-hydroxyestrone ratio, a known biomarker for the reduction of breast cancer risk I3C also stimulates detoxification enzymes in the gut and liver I3C is generally well tolerated when taken orally it may, however, promote tumor growth in animals that have been exposed to carcinogens because it induces cytochrome P450 enzymes, I3C may interact with several medications 13 14. Nuclear factors modulated by I3C Four nuclear transcription factors interact with I3C and DIM estrogen receptor (ER) Sp1 nuclear factor B (NFB) aryl hydrocarbonreceptor (AhR)These may account for changes in downstream events in normal and neoplastic cells.Y.S. Kim, J.A. Milner. J Nutri Biochem 16 (2005) 657314 15. DIM Resource Centre, University of California at Berkeley15 16. DIM Resource Centre, University of California at Berkeley16 17. 17 DIM Resource Centre, University of California at Berkeley 18. Chemical structures of I3C and DIM and summary of their key modulatory effects on hormone responsiveness and receptor signaling in human cancer cells. EGF, Epidermal growth factor. 18 19. I3C Targets Multiple Pathways I3C and DIM have potent growth inhibitory and apoptosis inducing effects on human and animal cancer cells by targeting multiple cellular signaling pathways in vitro Their inhibitory effects on cancer cell growth are through the modulation of genes that are related to the control of cell proliferation, cell cycle, apoptosis, signal transduction, oncogenesis, and transcription regulation Their pleiotropic effects on cancer cells through targeting multiple cellular signaling pathways including NF-B, Akt, MAPK, Wnt, Notch, and androgen receptor (AR) Could be useful either alone or in combination with conventional therapeutics for the prevention of tumor progression and/or treatment of human malignancies Sarkar & Li, Cancer Treat Rev. 2009 November ; 35(7): 597607 Chinni SR et al., Oncogene 2001;20:292736 Li Y et al., J Nutr 2003;133:10119 Mukhopadhyay A et al., Oncogene 2001;20:7597609. Shao ZM et al., Int J Cancer 2002;98:23440.19 20. NF-B, Akt, and Notch signaling pathways altered by isoflavone, I3C, DIM, and curcumin 20 21. Targeting Multiple Signals Inactivation of NF-B is mechanistically linked with growth inhibitory and apoptosis promoting activity Inhibition of NF-B through modulation of IKK and IBInhibition of Akt signaling (Akt responsible for cancer development and progression) Decreased phosphorylated Akt protein at Ser473 and the Akt kinase activityinhibition of Wnt signaling By up-regulating GSK-3, enhanced GSK-3 binding to -catenin, and increased the phosphorylation of -cateninAlso inhibitory effects on Notch signaling, resulting in the inhibition of cancer cell growth Sarkar & L