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.
Indole-3-carbinol, found in Brassica species vegetables (such as cabbage, cauliflower, and brussels spouts), exhibits antitumor effects through poorly defined mechanisms. Because several genes that regulate apoptosis, proliferation, and metastasis are regulated by nuclear factor-kappaB (NF-kappaB), we postulated that indole-3-carbinol must mediate its activity through NF-kappaB modulation. We demonstrated that indole-3-carbinol suppressed constitutive NF-kappaB activation and activation induced by tumor necrosis factor (TNF), interleukin-1beta (IL-1beta), phorbol 12-myristate 13-acetate (PMA), lipopolysaccharide (LPS), and cigarette smoke; the suppression was not cell type specific, because activation was inhibited in myeloid, leukemia, and epithelial cells. This activation correlated with the sequential suppression of the IkappaBalpha kinase, IkappaBalpha phosphorylation, IkappaBalpha ubiquitination, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, p65 acetylation, and NF-kappaB-dependent reporter gene expression. The NF-kappaB-regulated gene products cyclin D1, cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9), survivin, inhibitor-of-apoptosis protein-1 (IAP1), IAP2, X chromosome-linked IAP (XIAP), Bcl-2, Bfl-1/A1, TNF receptor-associated factor-1 (TRAF1), and Fas-associated death domain protein-like interleukin-1beta-converting enzyme inhibitory protein (FLIP) were all down-regulated by indole-3-carbinol. This down-regulation led to the potentiation of apoptosis induced by cytokines and chemotherapeutic agents. Indole-3-carbinol suppressed constitutive NF-kappaB activation in mononuclear cells derived from bone marrow of acute myelogenous leukemia patients, and this correlated with inhibition of cell growth. Overall, our results indicated that indole-3-carbinol inhibits NF-kappaB and NF-kappaB-regulated gene expression and that this mechanism may provide the molecular basis for its ability to suppress tumorigenesis.
Takada
Yasunari
Y
Cytokine Research Laboratory, Department of Experimental Therapeutics, Section of Molecular Hematology and Therapy, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Andreeff
Michael
M
Aggarwal
Bharat B
BB
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D019169:Jurkat Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008954:Models, Biological; D022423:Myeloid Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism
D000970:Antineoplastic Agents; D020672:I-kappa B Proteins; D007211:Indoles; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D000072000:NF-KappaB Inhibitor alpha; C016517:indole-3-carbinol; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human