New cancer drugs targeting the biosynthesis of estrogens and androgens

Abstract

The enzymes involved in the synthesis of steroids are very interesting therapeutic targets. By reducing the levels of androgens and estrogens that stimulate the proliferation of cancer cells, a potent and selective inhibitor of a key-steroidogenic enzyme may become an alternative or a complementary strategy to the use of an antiandrogen or an antiestrogen for the treatment of prostate cancer or breast and endometrial cancers, respectively. Five enzymes, namely 17a-hydroxylase 17a-lyase, aromatase, 17b-hydroxysteroid dehydrogenases, 5a-reductases, and steroid sulfatase were especially studied and found to be interesting targets for the development of inhibitors as potential cancer drugs. The present review will summarize the role of these five enzymes and their inhibitors with a special highlight about the molecules more recently reported in the literature and exhibiting dual therapeutic action. Drug Dev Res 69: 304-318, 2008.

Crateva adansonii DC, an African ethnomedicinal plant, exerts cytotoxicity in vitro and prevents experimental mammary tumorigenesis in vivo

“…Its main goal is to stop cell proliferation, which is very important due to the fact that hormone-dependent breast cancers are the most prevalent (Clarke et al, 2003). There are three types of hormone therapy: the inhibitive hormone therapy with antiaromatase, the hormone therapy with antiestrogens, and hormone therapy coupled with synthetic progestatives (Poirier, 2008). However, large clinical trials have mentioned serious side effects like the increased risk in the development of endometrial cancer and cardiovascular diseases (Lazzeroni et al, 2012).…”

A New Nonestrogenic Steroidal Inhibitor of 17β-Hydroxysteroid Dehydrogenase Type I Blocks the Estrogen-Dependent Breast Cancer Tumor Growth Induced by Estrone

“…To date, there are 15 known isoforms of 17b-HSDs, which are cofactor-dependent (8), and all of these belong to the SDR family except 17b-HSD5, which is an AKR enzyme (1). The enzymatic activities associated with the different isoforms of 17b-HSDs are widespread in human tissues, not only in classic steroidogenic tissues, such as the testis, ovary, and placenta, but also in a large series of peripheral intracrine tissues (9). More importantly, each 17b-HSD isoform has a specific tissue distribution (10)(11)(12) and displays a selective substrate affinity, and moreover, in intact cells, its activity is unidirectional (reductive or oxidative; refs.…”

“…For cancer therapy, the inhibition of oxidative 17b-HSDs, the transformation of the most proliferative cell form (hydroxyl) of hormone into a less potent form (ketone), is not suitable. In contrast, the selective inhibition of reductive 17b-HSDs involved in the transformation of ketosteroids into hydroxysteroids must be encouraged (9). The most extensively characterized of 17b-HSDs is type I (17b-HSD1), which catalyzes the NAD(P)H-dependent reduction of estrone (E1) into the potent estrogen estradiol (E2; Fig.…”

Contribution to the development of inhibitors of 17β-hydroxysteroid dehydrogenase types 1 and 7: Key tools for studying and treating estrogen-dependent diseases

“…The development of potent inhibitors of aromatase and 5␣-reductase [29], two key steroidogenic enzymes, and their use in clinical applications thereafter, stimulated the research on inhibitors of other key steroidogenic enzymes. We started a research program in 1991 aimed at developing inhibitors of 17␤-HSDs.…”