In earlier studies, we demonstrated the efficacy of
indole-3-carbinol (I3C) against
lung adenocarcinoma in A/J mice. However, these effects were accompanied by reductions in
body weight gain. We therefore assessed if combinations of low doses of I3C with
silibinin could inhibit lung
tumorigenesis without causing undesirable side effects. In in vitro assays with A549 and H460
lung cancer cells, exposure of the cells to a mixture of low concentrations of I3C (50 μM) plus
silibinin (50 μM) for 72 h caused inhibition of cell growth and
extracellular signal-regulated kinase (ERK) and Akt activation and induction of apoptosis, whereas the individual agents did not have any effect. In mice pretreated with
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and given I3C (10 μmol/g diet) plus
silibinin (7 μmol/g diet), multiplicities of
tumors on the surface of the lung and
adenocarcinoma were reduced by 60 and 95%, respectively. The individual effects of I3C and
silibinin were relatively weaker: 43 and 36% reductions, respectively, in the multiplicity of
tumors on the surface of the lung and 83 and 50% reductions, respectively, in the number of
adenocarcinoma. Also, the expression of phospho-Akt, phospho-ERK and
cyclin D1 and
poly (ADP-ribose) polymerase cleavage were strongly modulated by I3C plus
silibinin than by I3C or
silibinin alone, suggesting that the chemopreventive activities of the mixture could be mediated, at least partly, via modulation of the level of these
proteins. Taken together, our findings showed that mixtures of I3C and
silibinin are more potent than the individual compounds for the
chemoprevention of
lung cancer in A/J mice.