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3,3'-diindolylmethane suppresses 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and tumor promotion in mouse skin via the downregulation of inflammatory mediators. Kim EJ, Park H, Kim J, Park JH. Center for Efficacy Assessment and Development of Functional Foods and Drugs, Hallym University, Chuncheon, Korea. Mol Carcinog. 2010 Jul;49(7):672-83. 3,3'-Diindolylmethane (DIM) is a major acid-condensation product of indole-3-carbinol and is present in cruciferous vegetables. In this study, we evaluated the effects of DIM on antiinflammatory and antitumor promotion activity in mouse skin and explored the relevant mechanisms. When 12-O-tetradecanoylphorbol-13-acetate (TPA) was applied topically to the mouse ear to induce inflammation, DIM pretreatment effectively inhibited TPA-induced ear edema formation. To evaluate the mechanisms underlying DIM's antiinflammatory effects, DIM was topically treated to the shaved backs of mice 30 min before TPA treatment. DIM inhibited the TPA-induced increases in the expression of cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), chemokine (C-X-C motif) ligand (CXCL) 5, and interleukin (IL)-6 in mouse skin. DIM also inhibited nuclear factor-kappa B (NF-kappaB)'s DNA binding activity, the nuclear translocation of p65, and the degradation of inhibitor of kappaB (IkappaB) alpha in TPA-stimulated mouse skin. Furthermore, DIM reduced TPA-induced increases in the activity of extracellular signal regulated protein kinase (ERK)-1/2 and IkappaB kinase (IKK). When mouse skin papillomas were initiated via the topical application of 7,12-dimethylbenz[alpha]anthracene (DMBA) and promoted with repeated topical applications of TPA, repeated topical applications of DIM prior to each TPA treatment significantly suppressed the incidence and multiplicity of the papillomas. DIM also reduced the expression of COX-2 and iNOS, ERK phosphorylation, and the nuclear translocation of p65 in papillomas. Collectively, these results show that DIM exerts antiinflammatory and chemopreventive effects in mouse skin via the downregulation of COX-2, iNOS, CXCL5, and IL-6 expression, which may be mediated by reductions in NF-kappaB activation. PMID: 20564344 [PubMed - indexed for MEDLINE] 3,3'-Diindolylmethane attenuates experimental arthritis and osteoclastogenesis. Dong L, Xia S, Gao F, Zhang D, Chen J, Zhang J. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China. Biochem Pharmacol. 2010 Mar 1;79(5):715-21. 3,3'-Diindolylmethane (DIM) is a natural compound formed during the autolysis of glucobrassicin present in Brassica food plants. This study aimed to investigate the therapeutic efficacies of DIM on experimental arthritis. The effects of DIM on experimental arthritis were examined on a rat model of adjuvant-induced arthritis (AIA), with daily AIA paw swelling observation and histological/radiographic analysis. To elucidate the possible mechanisms of its action, serum cytokine levels as well as the expression of receptor activator for nuclear factor kappa B ligand (RANKL) in infected tissues were subsequently analyzed. The impact of DIM on osteoclastogenesis was further investigated on a mouse model of endotoxin-induced bone resorption (EIBR) and in vitro cultures of fibroblast-like cells and osteoblasts, with RANKL expression being evaluated with great interest. The administration of DIM was demonstrated to attenuate AIA in animal models, as judged by clinical and histologic indices of inflammation and tissue damage. On the one hand, DIM could reduce the expression of several inflammatory cytokines, which was, however, not adequate to prevent the development of the arthritis. On the other hand, DIM was shown to effectively inhibit the expression of RANKL, leading to the blockade of osteoclastogenesis and consequently an alleviation of experimental arthritis. Further in vitro and in vivo studies confirmed the inhibition of RANKL by DIM. DIM has shown anti-arthritis activity in animal models via inhibiting the expression of RANKL, and thus may offer potential treatments for arthritis and associated disorders. 2009 Elsevier Inc. All rights reserved. PMID: 19854159 [PubMed - indexed for MEDLINE] 3,3'-diindolylmethane attenuates colonic inflammation and tumorigenesis in mice. Kim YH, Kwon HS, Kim DH, Shin EK, Kang YH, Park JH, Shin HK, Kim JK. Center for Efficacy Assessment and Development of Functional Foods and Drugs, Hallym University, Chuncheon, South Korea. Inflamm Bowel Dis. 2009 Aug;15(8):1164-73. BACKGROUND: 3,3-Diindolylmethane (DIM) is a major in vivo product of acid-catalyzed oligomerization of indole-3-carbinol (I3C) derived from Brassica food plants. Although DIM is known as a chemopreventive and chemotherapeutic phytochemical, the effects of DIM on inflammation in vivo are still unknown. In the present study we investigated the antiinflammatory effects of DIM on experimental colitis and colitis-associated colorectal carcinogenesis. METHODS: To determine if DIM has an antiinflammatory effect in vivo, we examined the therapeutic effects of DIM in dextran sodium sulfate (DSS)-induced experimental colitis and colitis-associated colon carcinogenesis induced by azoxymethane (AOM)/DSS in BALB/c mice. RESULTS: Treatment with DIM significantly attenuated loss of body weight, shortening of the colon, and severe clinical signs in a colitis model. This was associated with a remarkable amelioration of the disruption of the colonic architecture and a significant reduction in colonic myeloperoxidase activity and production of prostaglandin E(2), nitric oxide, and proinflammatory cytokines. Further, DIM administration dramatically decreased the number of colon tumors in AOM/DSS mice. CONCLUSIONS: These results suggest that DIM-mediated antiinflammatory action at colorectal sites may be therapeutic in the setting of inflammatory bowel disease and colitis-associated colon cancer. PMID: 19334074 [PubMed - indexed for MEDLINE] Targeting of aryl hydrocarbon receptor-mediated activation of cyclooxygenase-2 expression by the indole-3-carbinol metabolite 3,3'-diindolylmethane in breast cancer cells. Degner SC, Papoutsis AJ, Selmin O, Romagnolo DF. Department of Nutritional Sciences, University of Arizona, Tucson, AZ 85721, USA. J Nutr. 2009 Jan;139(1):26-32. Epub 2008 Dec 3. Ligands of the aryl hydrocarbon receptor (AhR) include the environmental xenobiotic 2,3,7,8 tetrachlorodibenzo(p)dioxin (TCDD), polycyclic aryl hydrocarbons, and the dietary compounds 3, 3'-diindolylmethane (DIM), a condensation product of indol-3-carbinol found in Brassica vegetables, and the phytoalexin resveratrol (RES). The AhR and its cofactors regulate the expression of target genes at pentameric (GCGTG) xenobiotic responsive elements (XRE). Because the activation of cyclooxygenase-2 (COX-2) expression by AhR ligands may contribute to inflammation and tumorigenesis, we investigated the epigenetic regulation of the COX-2 gene by TCDD and the reversal effects of DIM in MCF-7 breast cancer cells. Results of DNA binding and chromatin immunoprecipitation (ChIP) studies documented that the treatment with TCDD induced the association of the AhR to XRE harbored in the COX-2 promoter and control CYP1A1 promoter oligonucleotides. The TCDD-induced binding of the AhR was reduced by small-interfering RNA for the AhR or the cotreatment with synthetic (3-methoxy-4-naphthoflavone) or dietary AhR antagonists (DIM, RES). In time course ChIP studies, TCDD induced the rapid (15 min) occupancy by the AhR, the histone acetyl transferase p300, and acetylated histone H4 (AcH4) at the COX-2 promoter. Conversely, the cotreatment of MCF-7 cells with DIM (10 micromol/L) abrogated the TCDD-induced recruitment of the AhR and AcH4 to the COX-2 promoter and the induction of COX-2 mRNA and protein levels. Taken together, these data suggest that naturally occurring modulators of the AhR such as DIM may be effective agents for dietary strategies against epigenetic activation of COX-2 expression by AhR agonists. Inhibition of nuclear translocation of nuclear factor-{kappa}B contributes to 3,3'-diindolylmethane-induced apoptosis in breast cancer cells. Rahman KW, Sarkar FH. Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA. Carcinogenesis. 2005 Apr;26(4):771-8. Epub 2005 Jan 20. Dietary indole-3-carbinol (I3C), a natural compound present in vegetables of the genus Brassica, showed clinical benefits and caused apoptosis in breast cancer cells. Our laboratory and others have shown that I3C induces apoptosis in breast cancer cells mediated by inactivation of Akt and nuclear factor-kappaB (NF-kappaB) pathway. 3,3'-Diindolylmethane (DIM), a major in vivo acid-catalyzed condensation product of I3C, also showed some benefit in breast cancer. However, the precise molecular mechanism(s) by which DIM induces apoptosis in breast cancer cells has not been fully elucidated. Hence, we investigated whether DIM-induced apoptosis of breast cancer cells could also be mediated by inactivation of Akt and NF-kappaB. We found that DIM induces apoptotic processes in MCF10A derived malignant (MCF10CA1a) cell lines but not in nontumorigenic parental MCF10A cells. DIM specifically inhibits Akt kinase activity and abrogates the epidermal growth factor-induced activation of Akt in breast cancer cells, similar to those observed for I3C. We also found that DIM reduces phosphorylation of IkappaBalpha, an inhibitor of NF-kappaB. Our confocal microscopy study clearly showed that DIM blocks the translocation of p65, a subunit of NF-kappaB to the nucleus. DNA binding analysis and transfection studies with IkappaB kinase cDNA revealed that overexpression of IkappaB kinase mediates IkappaBalpha phosphorylation, which activates NF-kappaB, and this activation was completely abrogated by DIM treatment. Taken together, these results showed for the first time that the inactivation of Akt and NF-kappaB activity also plays important roles in DIM-induced apoptosis in breast cancer cells, which seems to be more relevant to in vivo situations. PMID: 15665315 [PubMed - indexed for MEDLINE]
3,3'-Diindolylmethane inhibits angiogenesis and the growth of transplantable human breast carcinoma in athymic mice. Chang X, Tou JC, Hong C, Kim HA, Riby JE, Firestone GL, Bjeldanes LF. Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA. Carcinogenesis. 2005 Apr;26(4):771-8. Epub 2005 Jan 20. Studies have linked the consumption of broccoli and other cruciferous vegetables to a reduced risk of breast cancer. The phytochemical indole-3-carbinol (I3C), present in cruciferous vegetables, and its major acid-catalyzed reaction product 3,3'-diindolylmethane (DIM) have bioactivities relevant to the inhibition of carcinogenesis. In this study, the effect of DIM on angiogenesis and tumorigenesis in a rodent model was investigated. We found that DIM produced a concentration-dependent decrease in proliferation, migration, invasion and capillary tube formation of cultured human umbilical vein endothelial cells (HUVECs). Consistent with its antiproliferative effect, which was significant at only 5 microM DIM, this indole caused a G1 cell cycle arrest in actively proliferating HUVECs. Furthermore, DIM downregulated the expression of cyclin-dependent kinases 2 and 6 (CDK2, CDK6), and upregulated the expression of CDK inhibitor, p27(Kip1), in HUVECs. We observed further in a complementary in vivo Matrigel plug angiogenesis assay that, compared with vehicle control, neovascularization was inhibited up to 76% following the administration of 5 mg/kg DIM to female C57BL/6 mice. Finally, this dose of DIM also inhibited the growth of human MCF-7 cell tumor xenografts by up to 64% in female athymic (nu/nu) mice, compared with the vehicle control. This is the first study to show that DIM can strongly inhibit the development of human breast tumor in a xenograft model and to provide evidence for the antiangiogenic properties of this dietary indole. PMID: 15661811 [PubMed - indexed for MEDLINE]
Hestermann EV, Brown M. Department of Molecular Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. Mol Cell Biol. 2003 Nov;23(21):7920-5. Aryl hydrocarbon receptor (AHR) is a transcription factor whose activity is regulated by environmental agents, including several carcinogenic agonists. We measured recruitment of AHR and associated proteins to the human cytochrome P4501A1 gene promoter in vivo. Upon treatment with the agonist beta-naphthoflavone, AHR is rapidly associated with the promoter and recruits the three members of the p160 family of coactivators as well as the p300 histone acetyltransferase, leading to recruitment of RNA polymerase II (Pol II) and induction of gene transcription. AHR, coactivators, and Pol II cycle on and off the promoter, with a period of approximately 60 min. In contrast, the chemopreventative AHR ligand 3,3'-diindolylmethane promotes AHR nuclear translocation and p160 coactivator recruitment but, remarkably, fails to recruit Pol II or cause histone acetylation. This novel mechanism of receptor antagonism may account for the antitumor properties of chemopreventative compounds targeting the AHR.
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