Silibinin is a polyphenolic flavonoid isolated from the milk thistle (Silybum marianum) and is reported to exhibit anticancer properties. Recently, it has been reported that silibinin inhibits hypoxia-inducible factor-1 alpha (HIF-1 alpha) expression in cancer cells. However, the precise mechanism by which silibinin decreases HIF-1 expression is not fully understood. In this study, silibinin inhibited basal and hypoxia induced expression levels of HIF-1 alpha protein in LNCaP and PC-3 prostate cancer cells, while the rate of HIF-1 alpha protein degradation and mRNA levels were not affected. We found that the decrease in HIF-1 protein by silibinin correlated with suppression of de novo synthesis of HIF-1 alpha protein. Silibinin inhibited global protein synthesis coincided with reduction of eIF4F complex formation and induction of phosphorylation of the translation initiation factor 2 alpha (eIF-2 alpha) which can cause inhibition of general protein synthesis. These results suggest that silibinin's activity to inhibit HIF-1 alpha protein expression is associated with the suppression of global protein translation. (C) 2009 Elsevier Inc. All rights reserved.