Plant-derived 3,3'-Diindolylmethane is a strong androgen antagonist in human prostate cancer cells.
3,3'-Diindolylmethane (DIM) is a major digestive product of indole-3-carbinol, a potential anticancer component of cruciferous vegetables. Our results indicate that DIM exhibits potent antiproliferative and antiandrogenic properties in androgen-dependent human prostate cancer cells. DIM suppresses cell proliferation of LNCaP cells and inhibits dihydrotestosterone (DHT) stimulation of DNA synthesis. These activities were not produced in androgen-independent PC-3 cells. Moreover, DIM inhibited endogenous PSA transcription and reduced intracellular and secreted PSA protein levels induced by DHT in LNCaP cells. Also, DIM inhibited, in a concentration-dependent manner, the DHT-induced expression of a prostate-specific antigen promoter-regulated reporter gene construct in transiently transfected LNCaP cells. Similar effects of DIM were observed in PC-3 cells only when these cells were co-transfected with a wild-type androgen receptor expression plasmid. Using fluorescence imaging with green fluorescent protein androgen receptor and Western blot analysis, we demonstrated that DIM inhibited androgen-induced androgen receptor (AR) translocation into the nucleus. Results of receptor binding assays indicated further that DIM is a strong competitive inhibitor of DHT binding to the AR. Results of structural modeling studies showed that DIM is remarkably similar in conformational geometry and surface charge distribution to an established synthetic AR antagonist, although the atomic compositions of the two substances are quite different. Taken together with our published reports of the estrogen agonist activities of DIM, the present results establish DIM as a unique bifunctional hormone disrupter. To our knowledge, DIM is the first example of a pure androgen receptor antagonist from plants.
Le
Hien T
HT
Department of Nutritional Sciences and Toxicology, The University of California, Berkeley, California 94720-3104, USA. lfb@nature.berkeley.edu
Schaldach
Charlene M
CM
Firestone
Gary L
GL
Bjeldanes
Leonard F
LF
D000230:Adenocarcinoma; D000726:Androgen Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000813:Anilides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D013196:Dihydrotestosterone / Q000378:metabolism / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D015741:Metribolone / Q000378:metabolism / Q000494:pharmacology; D009570:Nitriles; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms; D012333:RNA, Messenger / Q000032:analysis; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D045165:Testosterone Congeners / Q000378:metabolism / Q000494:pharmacology; D014105:Tosyl Compounds; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000502:physiology; D014675:Vegetables / Q000737:chemistry
D000726:Androgen Antagonists; D000813:Anilides; D016588:Anticarcinogenic Agents; D007211:Indoles; D009570:Nitriles; D012333:RNA, Messenger; D011944:Receptors, Androgen; D045165:Testosterone Congeners; D014105:Tosyl Compounds; D013196:Dihydrotestosterone; D015741:Metribolone; D004247:DNA; C053541:bicalutamide; D017430:Prostate-Specific Antigen; C016392:3,3'-diindolylmethane