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ANTI-ANDROGENIC MECHANISM OF A NEW COMPOUND
Phone: (858) 638-7230
Phone: (858) 638-7230
Type: Domestic Nonprofit Research Organization
DESCRIPTION (provided by applicant): Androgen blockage therapy may relieve the symptom of an advanced, localized prostate tumor; however, once the tumor evolves into a hormone-refractory stage, there is no effective treatment. A continuous activation of AR by antiandrogens (used in androgen blockage therapy) or other "nonconventional" agonists may contribute to prostate cancer progression in patients after androgen deprivation. Conceptually, pharmacological agents blocking AR function evoked by not only testicular androgens but also other agonists would have a superior capacity to decrease prostate cancer incidence at both the androgen-sensitive and -insensitive stages. We recently found that a derivative of diferuloylmethane (Compound 4) inhibited dihydrotestosterone-induced androgen receptor transactivation in human prostate cancer cells. This agent also suppressed dihydrotestosterone-induced LNCaP cell growth. Furthermore, Compound 4 was effective in decreasing LNCaP cell growth and AR transactivation stimulated by hydroxyflutamide, a widely used antiandrogen. Based upon these preliminary data, we propose in this study to:
(1) Further test whether Compound 4 abolishes AR function elicited by cyproterone acetate, estradiol, dehydroepiandrosterone, and androstenediol. These antiandrogen or steroid hormones have been documented to have residual AR agonist activity and may exist in significant amounts in patients after androgen blockage therapy.
(2) Explore the mechanisms of action of Compound 4 to antagonize the AR. Compound 4 may disrupt the AR pathway at multiple steps. In this preliminary study, we will examine the most likely mechanisms- whether Compound 4 blocks androgen-induced biological response via a down-regulation of AR expression, or via a competitive suppression of testicular androgens' binding to the receptor.
The discovery of a novel antiandrogen capable of preventing both androgen-dependent and androgen-independent prostate cancer may have a direct impact in clinical application.
* Information listed above is at the time of submission. *