3,3′-diindolylmethane downregulates pro-survival pathway in hormone independent prostate cancer

Epidemiological evidences suggest that the progression and promotion of prostate cancer (CaP) call be modulated by diet. Since all men die with prostate cancer rather than of the disease, it is of particular interest to present or delay the progression of the disease by chemopreventive strategies. We have been studying the anticancer properties of compounds present in cruciferous vegetables such as indole-3-carbinol (13C). Diindolylmethane (DIM) is a dimer of 13C that is formed under acidic Conditions Ond unlike 13C is more stable with higher anti-cancer effects. In the present report. we demonstrate that DIM is a potent agent compared to 13C ill the hormone independent DU 145 CaP cells. The anti-prostate cancer effect is mediated bN the inhibition of the Akt signal transduction pathway as DIM, in sharp contrast to 13C. induces the downregulation of Akt. p-Akt. and 1113 kinase. DIM also induced a G1 arrest in DU 145 cells by flow cytometry and downstream concurrent inhibition of cell cycle parameter, such as cyclin D1. cdk4. and cdk6. Our data suggest a need for further development of DIM, as a chemopreventive agent for CaP, which justifies epidemiological evidences and molecular targets that are determinants for CaP dissemination/progression. The ingestion of DIM may benefit Call patients and reduce disease recurrence by eliminating micro-metastases that may be present ill patient, who undergo radical prostatectomy. (c) 2005 Elsevier Inc. All rights reserved.