Combinations of indole-3-carbinol and silibinin suppress inflammation-driven mouse lung tumorigenesis by modulating critical cell cycle regulators

Jung Min Song, Xuemin Qian, Kalkidan Molla, Fistum Teferi, Pramod Upadhyaya, Gerry O'Sullivan, Xianghua Luo, Fekadu Kassie

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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 (>1.0 mm) 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.

Original languageEnglish (US)
Pages (from-to)666-675
Number of pages10
JournalCarcinogenesis
Volume36
Issue number6
DOIs
StatePublished - 2015

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