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Inhibition of 3 beta-hydroxysteroid-dehydrogenase: an approach for prostate cancer treatment?
A A Geldof1, I Dijkstra, D W Newling
1Department of Endocrinology, Academisch Ziekenhuis Vrije Universiteit, Amsterdam, The Netherlands.
Abstract:
Over 80% of clinically manifested prostate cancers respond to androgen withdrawal. Several alternatives to castration have been explored. Since a growth promoting role for androstenedione has been suggested, we investigated the effect of inhibition of 3 beta-hydroxy-steroid-dehydrogenase (3 beta-HSD), a key enzyme involved in the biosynthesis of practically all steroids. In a previous study a reduced proliferation rate of androgen responsive R3327-H tumor was demonstrated after in vivo treatment with 17 beta-N,N-diethylcarbamoyl-4-aza-5 alpha-androstan-3-one (4MA) - a putative 5 alpha-reductase inhibitor. In the present investigation 3 beta-HSD enzyme activity derived from human placenta, testis and ovarian cancer cell line and from rat testis was determined using radiolabeled dehydroepiandrosterone (DHEA) or pregnenolone. Among different synthetic compounds known to interfere with steroidogenesis, only 4MA was shown to potently inhibit in vitro 3 beta-HSD activity from all tissue sources. 4MA was administered to male Copenhagen rats bearing R3327-H androgen dependent prostate tumors and levels of different androgens in serum and prostate tumor were measured using reversed phase HPLC and radioimmunoassay. The decreased content of androstenedione in serum and tumor tissue with DHEA accumulation in prostate tumor tissue showed an effective 3 beta-HSD inhibition by 4MA occurring in vivo as well. These observations unequivocally demonstrate a 3 beta-HSD inhibiting effect of 4MA in vitro as well as in vivo and point to a role for androstenedione in the promotion of cell proliferation in androgen sensitive tumors. 3 beta-HSD dependent androstenedione production could thus constitute a proper target -eventually combined with other endocrine treatment - for the treatment of hormone dependent prostate cancer.
Insights
The study found that 17 beta-N,N-diethylcarbamoyl-4-aza-5 alpha-androstan-3-one (4MA) inhibits 3 beta-hydroxy-steroid-dehydrogenase (3 beta-HSD) in vitro and in vivo. This inhibition of 3 beta-HSD may offer a new therapeutic target for prostate cancer treatment.
Area of Science:
- Endocrinology
- Oncology
- Biochemistry
Background:
- Prostate cancer often relies on androgens for growth.
- Androstenedione may promote tumor cell proliferation.
- 3 beta-hydroxy-steroid-dehydrogenase (3 beta-HSD) is crucial for steroid biosynthesis.
Purpose of the Study:
- To investigate the inhibitory effect of 17 beta-N,N-diethylcarbamoyl-4-aza-5 alpha-androstan-3-one (4MA) on 3 beta-HSD.
- To determine if 4MA can inhibit 3 beta-HSD activity in vivo and impact androgen levels in prostate tumors.
Main Methods:
- Assessed 3 beta-HSD enzyme activity using radiolabeled substrates (DHEA, pregnenolone) in various human and rat tissues.
- Screened synthetic compounds for 3 beta-HSD inhibitory potential.
- Administered 4MA to rats with R3327-H prostate tumors and measured androgen levels via HPLC and radioimmunoassay.
Main Results:
- 4MA demonstrated potent inhibition of 3 beta-HSD activity across all tested tissue sources in vitro.
- In vivo administration of 4MA led to decreased androstenedione levels and increased DHEA accumulation in prostate tumors.
- These findings confirm 4MA's efficacy in inhibiting 3 beta-HSD both in vitro and in vivo.
Conclusions:
- 4MA effectively inhibits 3 beta-HSD, a key enzyme in androgen biosynthesis.
- Targeting 3 beta-HSD dependent androstenedione production presents a potential therapeutic strategy for hormone-dependent prostate cancer.
- Combined endocrine therapies targeting 3 beta-HSD may enhance prostate cancer treatment outcomes.