title: Combinations of indole-3-carbinol and silibinin suppress inflammation-driven mouse lung tumorigenesis by modulating critical cell cycle regulators.
abstract: Chronic inflammation is an important risk factor for lung cancer. Therefore, identification of chemopreventive agents that suppress inflammation-driven lung cancer is indispensable. We studied the efficacy of combinations of indole-3-carbinol (I3C) and silibinin (Sil), 20 µmol/g diet each, against mouse lung tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and driven by lipopolysaccharide (LPS), a potent inflammatory agent and constituent of tobacco smoke. Mice treated with NNK + LPS developed 14.7±4.1 lung tumors/mouse, whereas mice treated with NNK + LPS and given combinations of I3C and Sil had 7.1±4.5 lung tumors/mouse, corresponding to a significant reduction of 52%. Moreover, the number of largest tumors (>1.0mm) was significantly reduced from 6.3±2.9 lung tumors/mouse in the control group to 1.0±1.3 and 1.6±1.8 lung tumors/mouse in mice given I3C + Sil and I3C alone, respectively. These results were paralleled by significant reductions in the level of proinflammatory and procarcinogenic proteins (pSTAT3, pIκBα and COX-2) and proteins that regulate cell proliferation (pAkt, cyclin D1, CDKs 2, 4, 6 and pRB). Further studies in premalignant bronchial cells showed that the antiproliferative effects of I3C + Sil were higher than the individual compounds and these effects were mediated by targeting cyclin D1, CDKs 2, 4 and 6 and pRB. I3C + Sil suppressed cyclin D1 by reducing its messenger RNA level and by enhancing its proteasomal degradation. Our results showed the potential lung cancer chemopreventive effects of I3C + Sil in smokers/former smokers with chronic pulmonary inflammatory conditions.
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Song
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Xuemin
authors.initials: X
authors.lastname: Qian
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Kalkidan
authors.initials: K
authors.lastname: Molla
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Fistum
authors.initials: F
authors.lastname: Teferi
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Pramod
authors.initials: P
authors.lastname: Upadhyaya
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, USA and.
authors.forename: Gerry
authors.initials: G
authors.lastname: O Sullivan
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA, Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Xianghua
authors.initials: X
authors.lastname: Luo
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, USA and kassi012@umn.edu.
authors.forename: Fekadu
authors.initials: F
authors.lastname: Kassie
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D018890:Chemoprevention; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D004338:Drug Combinations; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis; D007211:Indoles / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy*; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008805:Mice, Inbred A; D000072000:NF-KappaB Inhibitor alpha; D009602:Nitrosamines / Q000009:adverse effects; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D011897:Random Allocation; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000096:biosynthesis; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*; D012906:Smoke / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016588:Anticarcinogenic Agents; C530105:Ccnd1 protein, mouse; D018797:Cell Cycle Proteins; D004338:Drug Combinations; D020672:I-kappa B Proteins; D007211:Indoles; D015850:Interleukin-6; D008070:Lipopolysaccharides; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D009602:Nitrosamines; D016160:Retinoblastoma Protein; D050796:STAT3 Transcription Factor; D012838:Silymarin; D012906:Smoke; C494087:Stat3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019938:Cyclin D1; D000072000:NF-KappaB Inhibitor alpha; D000077385:Silybin; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C016517:indole-3-carbinol; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; D018844:Cyclin-Dependent Kinases