Silibinin sensitizes human prostate carcinoma DU145 cells to cisplatin- and carboplatin-induced growth inhibition and apoptotic death

In several recent studies, we have shown that silibinin inhibits the growth of human prostate cancer cells (PICA) both in vitro and in vivo. Here, we investigated the effect of silibinin in combination with cisplatin and carboplatin on human PCA DU145 cell growth and apoptosis. Cisplatin alone at 2 mug/ml dose produced 48% cell growth inhibition, whereas a combination with 50-100 muM silibinin resulted in 63-80% (p<0.05-0.001) growth inhibition. Similarly, compared to 68% growth inhibition at 20 mug/ml carboplatin, addition of 50-100 muM doses of silibinin caused 80-90% inhibition (p<0.005-0.001). In the studies assessing the effect of these combinations on cell cycle progression, a combination of cisplatin or carboplatin with silibinin resulted in a stronger G2-M arrest, compared to these agents alone showing a moderate G2-M and G I arrests in case of cisplatin and silibinin, and a complete S phase arrest with carboplatin, respectively. A stronger G2-M arrest by these combinations was accompanied by a substantial decrease in the levels of cdc2, cyclin BI and cdc25C. Silibinin/platinum compound combinations were also effective in inducing apoptosis where cisplatin and carboplatin when combined with silibinin enhanced apoptosis from 8 to 15% and from 20 to 40%, respectively. Apoptosis induction was further confirmed by PARP and caspases 3, 9 and 7 whose cleaved levels were also enhanced by combination treatment. In addition, there was a significant increase in cytochrome c release in the cytosol following treatment of DU 145 cells with these combinations. Together, these results show a substantial increase in the efficacy of platinum compounds on human PCA cells, when combined with silibinin, which provide a rationale for further investigations with these combinations. (C) 2003 Wiley-Liss, Inc.