3,3'-Diindolylmethane downregulates pro-survival pathway in hormone independent prostate cancer.
Epidemiological evidences suggest that the progression and promotion of prostate cancer (CaP) can be modulated by diet. Since all men die with prostate cancer rather than of the disease, it is of particular interest to prevent 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 (I3C). Diindolylmethane (DIM) is a dimer of I3C that is formed under acidic conditions and unlike I3C is more stable with higher anti-cancer effects. In the present report, we demonstrate that DIM is a potent anti-proliferative agent compared to I3C in the hormone independent DU 145 CaP cells. The anti-prostate cancer effect is mediated by the inhibition of the Akt signal transduction pathway as DIM, in sharp contrast to I3C, induces the downregulation of Akt, p-Akt, and PI3 kinase. DIM also induced a G1 arrest in DU 145 cells by flow cytometry and downstream concurrent inhibition of cell cycle parameters 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 CaP patients and reduce disease recurrence by eliminating micro-metastases that may be present in patients who undergo radical prostatectomy.
Garikapaty
Venkata P S
VP
Department of Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA.
Ashok
Badithe T
BT
Tadi
Kiranmayi
K
Mittelman
Abraham
A
Tiwari
Raj K
RK
D000728:Androgens / Q000502:physiology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004261:DNA Replication / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D016193:G1 Phase / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D016196:S Phase / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D000728:Androgens; D016588:Anticarcinogenic Agents; D015415:Biomarkers; D006131:Growth Inhibitors; D007211:Indoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; C016517:indole-3-carbinol; D051057:Proto-Oncogene Proteins c-akt; C016392:3,3'-diindolylmethane