Suppression of Δ
            <sup>5</sup>
            -androstenediol-induced androgen receptor transactivation by selective steroids in human prostate cancer cells

Chang, Hong; Miyamoto, Hiroshi; Marwah, Padma; Lardy, Henry A.; Yeh, Shuyuan; Huang, Kuo Yuan; Chang, Chawnshang

doi:10.1073/pnas.96.20.11173

Cited by 37 publications

(24 citation statements)

References 28 publications

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“…Several 5 steroids derived from pregnenolone are active in humans and could activate the ancestral ER and PR. 5-Adiol (Kuiper et al, 1997) and 7-keto-DHEA and a 16-keto-derivative of 5-Adiol (Chang et al (1999) activate the mammalian ER. DHEA, pregnenolone and 7-hydroxy-pregnenolone are neurosteroids (Akawa et al, 1992, Compagnone andMellon, 1998;Baulieu and Robel, 1998).…”

Section: A Paradox the Er And Not The Pr Is Most Ancient: What Was Tmentioning

confidence: 99%

“…Moreover, these 7 -11 hydroxy-and 7 -hydroxy-steroids can be oxidized to 7-oxo-steroids [ Figure 4]. Support for the possibility that keto-5 steroids were ligands for the ancestral ER comes from the report by Chang et al (1999) that 100 nM 7-keto-DHEA and 16-keto derivative of 5-Adiol activated transcription mediated by the ER in MCF-7 breast cancer cells. These and other DHEA metabolites (e.g.…”

Section: A Paradox the Er And Not The Pr Is Most Ancient: What Was Tmentioning

confidence: 99%

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Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors

Baker

2004

Molecular and Cellular Endocrinology

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Abstract. Receptors for the adrenal and sex steroids arose by a series of gene duplications from an ancestral nuclear receptor in a primitive vertebrate, at least 540 million years ago. Sequence analysis indicates many steroidogenic and steroid-inactivating enzymes, including cytochrome P450s and hydroxysteroid dehydrogenases, arose at the same time. The estrogen receptor (ER) appears to be the ancestral steroid receptor. Initially, the redundant duplicated ER had a low specificity for its new ligand. This raises the question: "How was specificity for responses to different steroids regulated early in the evolution of steroid receptors?" Selective expression of these steroid-metabolizing enzymes provided specificity for different steroid responses in primitive vertebrates. 17 -hydroxysteroid dehydrogenase-type 1 (17 -HSD-type 1) and 17 -HSD-type 2, which preferentially catalyze the reduction and oxidation at C17 of androgens and estrogens, respectively, provide an example of this mechanism. Selective expression of either 17 -HSD-type 1 or 17 -HSD-type 2 can regulate synthesis or inactivation of androgens or estrogens in specific cells.Steroids also were important in the evolution of land animals, which began about 400 million years ago.Steroidogenic and steroid-inactivating enzymes were recruited to regulate steroid-mediated responses as organ function became more complex. For example, in the kidney 11 -HSD-type 2 prevents binding of glucocorticoids to the mineralocorticoid receptor, which is crucial for aldosterone-mediated regulation of electrolyte transport in the distal tubule. We propose that 5 steroids, such as dehydroepiandrosterone and its metabolites, were the ligands for the ancestral ER. Understanding the actions of 5 steroids in amphioxus and lamprey may shed light on adrenarche and neurosteroid actions in humans.

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Section: A Paradox the Er And Not The Pr Is Most Ancient: What Was Tmentioning

confidence: 99%

Section: A Paradox the Er And Not The Pr Is Most Ancient: What Was Tmentioning

confidence: 99%

Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors

Baker

2004

Molecular and Cellular Endocrinology

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“…We showed that many DHEA metabolites, including ADEK, possess some estrogen activity, 15,16 suggesting that ADEK might cause not only castration effect but also some side effects, such as cardiovascular toxicity in vivo. Because of these unfavorable side effects, estrogens (e.g., DES) are rarely used as first-line hormonal treatment in spite of the evidence suggesting an additional benefit, a direct cytotoxic effect of estrogens through both estrogen receptor (ER)-dependent and ER-independent pathways in prostate cancer cells.…”

Section: Hormone Specificity Of Steroid Derivativesmentioning

confidence: 98%

“…We have synthesized a number of steroids and tested their antiandrogenic activity vs. Adiol and DHT. 15,16 The most effective was 3b-acetoxyandrosta-1,5-diene-17-one ethylene ketal (ADEK), which inhibits both DHT-and Adiol-induced AR transcription, PSA expression and growth in prostate cancer cells. Significantly, ADEK has marginal androgenic activity and a strong AR coactivator, ARA70, which has been shown to enhance agonist activity of clinically used antiandrogens, 17,18 fails to induce it.…”

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confidence: 99%

Identification of steroid derivatives that function as potent antiandrogens

Miyamoto

Marwah

et al. 2005

Intl Journal of Cancer

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We have hypothesized that some steroid derivatives bind to the androgen receptor (AR) with very low androgenic activity and therefore potentially function as better AR antagonists than clinically used antiandrogens, such as flutamide. Indeed, we previously found such a compound, 3b-acetoxyandrosta-1,5-diene-17-one ethylene ketal (ADEK), with some estrogenic activity. Here we report the identification of 2 additional steroid derivatives, 3b-hydroxyandrosta-5,16-diene (HAD) and androsta-1,4-diene-3,17-dione-17-ethylene ketal (OAK), as new potent antiandrogens. Like ADEK, HAD and OAK could interrupt androgen binding to the AR and suppress both dihydrotestosterone-and androstenediol-induced transactivations of wild-type and mutant ARs in prostate cancer cells. These 2 compounds also inhibited prostate-specific antigen expression in LNCaP as well as growth of different AR-positive prostate cancer cell lines stimulated by androgen. Significantly, HAD and OAK had only marginal agonist effects, as compared to hydroxyflutamide. More importantly, in contrast to ADEK, OAK was shown to possess marginal estrogenic activity. These results strengthen our hypothesis and suggest that selective steroid derivatives could be potent antiandrogenic drugs with less unfavorable effects for the treatment of prostate cancer. ' 2005 Wiley-Liss, Inc.

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“…The human prostate cancer cell-line LNCaP expresses a mutant androgen receptor that allows it to respond to a wide variety of hormones, including the adrenal hormone AED (Miyamoto et al, 1998;Chang et al, 1999;Mizokami et al, 2004;He and Falany, 2007). Because of its potential role in sustaining prostate cancer cell growth after androgen deprivation therapy (ADT), we set out to determine whether a compound capable of inhibiting AEDstimulated LNCaP cell proliferation could be identified from a proprietary steroid library that was developed around the structure of AED.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of androstenediol-dependent LNCaP tumour growth by 17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235)

et al. 2009

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Androst-5-ene-3b, 17b-diol (AED) is an adrenal hormone that has been reported to sustain prostate cancer growth after androgen deprivation therapy (ADT). LNCaP cells express a mutated androgen receptor that confers the ability to respond not only to androgen but also to oestrogen and adrenal hormones such as AED, and thus provide a cell line useful for identifying compounds capable of inhibiting AED-stimulated cell growth. We sought to determine whether structurally related steroids could inhibit AED-stimulated LNCaP cell growth in vitro and tumour growth in vivo. We report here the identification of a novel androstane steroid, A considerable amount of research has been directed towards understanding factors that support the growth and expansion of prostate cancer during and after anti-androgen treatment. The observation that androgen deprivation results in increase in AR expression (Scher et al, 2004) highlights the importance of AR in this stage of disease and suggests that other ligands may be capable of binding and activating AR to drive tumour cell growth. It is well documented that mutations in the AR allow castration-resistant prostate cancer cells to utilise a broad spectrum of steroids, whose levels are not affected by anti-androgen therapy (Taplin et al, 1995). These include oestrogen, progesterone, glucocorticoid, and the adrenal hormone androst-5-ene-3b, 17b-diol (AED), a multipotent hormone that is an androgen and oestrogen precursor, with the ability to directly transactivate AR and ER in prostate cancer cells (Miyamoto et al, 1998;Maggiolini et al, 2004). Because AED's central role both as a precursor of DHT and a direct activator of the androgen receptor, we initiated studies to identify an inhibitor of AED signalling in hormonally sensitive tumour cells from a proprietary chemical library based on the structure of AED. Through the course of this work, compounds were identified that inhibited the proliferation of LNCaP cells stimulated by AED in vitro. Subsequent work to identify the most suitable pharmaceutical from this series of compounds resulted in the identification of HE3235 (17a-ethynyl-5a-androstan-3a, 17b-diol). Here, we present results showing that HE3235 blocks the growth of LNCaP cells by inducing apoptosis. Tumour studies have confirmed the in vivo activity of HE3235 against AED-stimulated LNCaP tumour cells. MATERIALS AND METHODS Synthesis of HE3235HE3235 was synthesised by reacting trimethylsilylazine with androsterone (DGP, Shanghai, China) in refluxing acetonitrile using saccharin catalyst. The trimethylsilyl-protected intermediate was subsequently reacted with ethynyltrimethylsilane activated with n-butyl lithium in tetrahydrofuran. The crude product was then recovered by slow addition of water to quench the reaction and filtration of the crude precipitate. The reaction product was purified to 499% pure HE3235 with a 67% of overall yield. LNCaP proliferation assayLNCaP-FGC, PC3, and DU145 cells were obtained from the American Type Tissue Collection (ATTC, Manassas, VA, USA). T...

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Suppression of Δ ⁵ -androstenediol-induced androgen receptor transactivation by selective steroids in human prostate cancer cells

Abstract: Our earlier report suggested that androst-5-ene-3␤,7␤-diol (⌬ 5 -androstenediol or Adiol) is a natural hormone with androgenic activity and that two potent antiandrogens, hydroxyf lutamide (Eulexin) and bicalutamide

Cited by 37 publications

References 28 publications

Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors

Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors

Identification of steroid derivatives that function as potent antiandrogens

Inhibition of androstenediol-dependent LNCaP tumour growth by 17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235)

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Suppression of Δ 5 -androstenediol-induced androgen receptor transactivation by selective steroids in human prostate cancer cells

Abstract: Our earlier report suggested that androst-5-ene-3␤,7␤-diol (⌬ 5 -androstenediol or Adiol) is a natural hormone with androgenic activity and that two potent antiandrogens, hydroxyf lutamide (Eulexin) and bicalutamide

Cited by 37 publications

References 28 publications

Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors

Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors

Identification of steroid derivatives that function as potent antiandrogens

Inhibition of androstenediol-dependent LNCaP tumour growth by 17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235)

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Product

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About

Suppression of Δ ⁵ -androstenediol-induced androgen receptor transactivation by selective steroids in human prostate cancer cells