Steroid-metabolizing enzymes as potential drug targets
The pathogenesis of hormone-dependent forms of cancer,
such as breast, prostate and endometrial cancers, correlates with higher local
concentrations of the estrogens and androgens. These drive cell proliferation,
and thus increase the opportunity for the accumulation of random genetic errors
that can lead to somatic mutations and malignant phenotypes. Enzymes involved
in the formation and inactivation of the potent hormones estradiol,
testosterone, 5a-dihydrotestosterone
and progesterone can regulate the occupancy of estrogen, androgen and
progesterone receptors and thus act as molecular switches at the pre-receptor
level. Such pre-receptor regulatory enzymes include the cytochrome P450s and
the hydroxysteroid dehydrogenases (HSDs). For several of these enzymes,
increased expression has been detected in diseased tissue, suggesting that
inhibitors of these enzymes will serve as selective intracrine modulators
(SIM). We are studying the HSDs from the AKR superfamily, AKR1C1 and AKR1C3,
which display varying ratios of 3-, 20- and 17-ketosteroid reductase
activities, and which thus inactivate 5a-DHT
and progesterone and activate estrone and androstenedione. We are also studying
17ß-HSD type 1 from the short-chain
dehydrogenase/ reductase (SDR) superfamily, which is responsible for estradiol
formation. In collaboration with Prof. Stanislav Gobec's group from the Faculty of
Pharmacy, University of Ljubljana, Slovenia, we are developing inhibitors of
recombinant AKR1C1, AKR1C3 and 17ß-HSD
type 1, which should be beneficial for the treatment of hormone-dependent
diseases.
