Suppression of androgen receptor expression by dibenzoylmethane as a therapeutic objective in advanced prostate cancer.
BACKGROUND
The androgen receptor (AR) plays an important role in the development and progression of prostate cancer. Functional AR expression persists in most cases of hormone-refractory prostate cancer and may play a role clinically in the progression from hormone-responsive to hormone-refractory or advanced prostate cancer. In order to combat the progression of this disease, one needs to identify new chemotherapeutic agents with novel mechanisms of action.


METHODS
In this study, we attempt to clarify the molecular mechanism by which dibenzoylmethane (DBM), a beta3-diketone, inhibits the growth of androgen-responsive human LNCaP prostate cancer cells and down-regulates expression of the AR. To this end, we treated LNCaP cells with different concentrations of DBM to monitor function and expression of AR and an AR-associated protein.


RESULTS
Previous studies showed that DBM could inhibit cell proliferation in LNCaP cells by arresting the cells at the G1 phase without causing cell death. Western blot and RT-PCR/Northern blot analyses showed a reduction in AR protein and mRNA expression by DBM in a dose-dependent manner. Furthermore, stable transfections of an androgen-independent human prostate cancer cell line, transfected with a full-length human AR cDNA sequence, showed that DBM down-regulated AR protein levels. DBM also inhibited the secretion of the AR-regulated tumor marker, prostate-specific antigen (PSA). Moreover, the relative binding affinity of DBM to AR was lower than that of the synthetic androgen R1881 (methyltrienolone) suggesting that DBM must suppress AR expression independent of an AR-DBM bound interaction.


CONCLUSIONS
These data provide new insights into how DBM regulates AR function and cell growth, as well as providing promising evidence to support DBM as a chemotherapeutic agent for prostate cancer through suppression of the function of the androgen receptor.
Jackson
Kimberly M
KM
Spelman College, Department of Chemistry, Box 1134, 350 Spelman Lane, SW, Atlanta, GA 30314, USA. kjackson@spelman.edu
Frazier
Monica C
MC
Harris
Wayne B
WB
D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology*; D006801:Humans; D008297:Male; D017430:Prostate-Specific Antigen / Q000032:analysis / Q000037:antagonists & inhibitors; D011471:Prostatic Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism
D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D047188:Chalcones; D012333:RNA, Messenger; D011944:Receptors, Androgen; C061481:dibenzoylmethane; D017430:Prostate-Specific Antigen