Control of cell proliferation by steroids: The role of 17HSDs

Vihko, Pirkko; Herrala, Annakaisa; Härkönen, Pirjo; Isomaa, Veli; Kaija, Helena; Kurkela, Riitta; Pulkka, Anitta E.

doi:10.1016/j.mce.2005.12.005

Cited by 50 publications

(41 citation statements)

References 50 publications

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“…This results in an increased level of E 2 that drives the proliferation of the tumour tissue via the ER. Several studies have indicated that patients with tumours that have high 17b-HSD1 expression have significantly shortened disease-free and overall survival (Gunnarsson et al 2005, Salhab et al 2006, Vihko et al 2006, suggesting that compounds which inhibit the activity of this enzyme may be of therapeutic benefit in the treatment of hormone-dependent breast cancer in post-menopausal patients .…”

Section: B-hsd1 Inhibitionmentioning

confidence: 99%

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

Day¹,

Tutill²,

Purohit³

et al. 2008

Endocrine Related Cancer

115

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Abstract17b-Hydroxysteroid dehydrogenases (17b-HSDs) are enzymes that are responsible for reduction or oxidation of hormones, fatty acids and bile acids in vivo, regulating the amount of the active form that is available to bind to its cognate receptor. All require NAD(P)(H) for activity. Fifteen 17b-HSDs have been identified to date, and with one exception, 17b-HSD type 5 (17b-HSD5), an aldo-keto reductase, they are all short-chain dehydrogenases/reductases, although overall homology between the enzymes is low. Although named as 17b-HSDs, reflecting the major redox activity at the 17b-position of the steroid, the activities of these 15 enzymes vary, with several of the 17b-HSDs able to reduce and/or oxidise multiple substrates at various positions. These activities are involved in the progression of a number of diseases, including those related to steroid metabolism. Despite the success of inhibitors of steroidogenic enzymes in the clinic, such as those of aromatase and steroid sulphatase, the development of inhibitors of 17b-HSDs is at a relatively early stage, as at present none have yet reached clinical trials. However, many groups are now working on inhibitors specific for several of these enzymes for the treatment of steroid-dependent diseases, including breast and prostate cancer, and endometriosis, with demonstrable efficacy in in vivo disease models. In this review, the recent advances in the validation of these enzymes as targets for the treatment of these diseases, with emphasis on 17b-HSD1, 3 and 5, the development of specific inhibitors, the models used for their evaluation, and their progress towards the clinic will be discussed.

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Section: B-hsd1 Inhibitionmentioning

confidence: 99%

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

Day¹,

Tutill²,

Purohit³

et al. 2008

Endocrine Related Cancer

115

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“…6,7 As mentioned above, many investigators have paid attention to the AR hypersensitivity-related mechanisms of development of androgen independence. On the other hand, steroid metabolic enzymes are still expressed in prostate cancer cells, although at the androgen-independent stage, the enzyme activity has been reported to be dramatically changed, 8 thus suggesting that steroidogenic processes of androgen metabolism are also important for the development of androgen independence. These two processes, namely AR hypersensitivityrelated development mechanisms and changes in the androgen steroidogenic processes are not mutually exclusive and could simultaneously operate in prostatic cells.…”

Section: Introductionmentioning

confidence: 99%

Importance of the intracrine metabolism of adrenal androgens in androgen-dependent prostate cancer

Suzuki

Nishiyama

Hara

et al. 2007

Prostate Cancer Prostatic Dis

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The metabolic pathways of androgens and processes by which androgens induce re-growth after androgen deprivation therapy in prostate cancer have not been fully elucidated. In this study, finasteride decreased PSA secretion in medium containing testosterone, androstenedione, androstenediol and dehydroepiandrosterone, whereas dihydrotestosterone (DHT)-and hydroxyflutamide-induced PSA production was not inhibited by finasteride in LNCaP-FGC cells. The present data show that adrenal androgen precursors do not directly interact with androgen receptors (ARs) but are converted to DHT via the intraprostatic metabolic pathways, resulting in the induction of LNCaP activity. This is the first report confirming this mechanism experimentally and also suggest the use of combined therapies that target ARs and prevent the formation of DHT within prostate cancer cells to achieve optimal therapeutic efficacy.

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“…These data suggest that 17 -HSD1 plays a major role in determining the gradient between the E2 concentrations in serum and peripheral tissues. An increased E2/E1 ratio by the 17 -HSD1 point out the pivotal role of 17 -HSD1 in breast cancer, ovarian tumor, endometriosis, endometrial hyperplasia and uterine leiomyoma [249,250]. Consequently, inhibition of 17 -HSD1 is considered as a valuable therapeutic approach for treatment of these deseases.…”

Section: β -Hydroxysteroid Dehydrogenase and Pregnancy -Role Of 11bmentioning

confidence: 99%

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review

Atanassova¹,

Koeva²

2012

Dehydrogenases

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Control of cell proliferation by steroids: The role of 17HSDs

Cited by 50 publications

References 50 publications

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

Importance of the intracrine metabolism of adrenal androgens in androgen-dependent prostate cancer

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review

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