Profiling adrenal 11β-hydroxyandrostenedione metabolites in prostate cancer cells, tissue and plasma: UPC2-MS/MS quantification of 11β-hydroxytestosterone, 11keto-testosterone and 11keto-dihydrotestosterone

Toit, Therina du; Bloem, Liezl M.; Quanson, Jonathan L.; Ehlers, Riaan; Serafin, Antonio; Swart, Amanda C.

doi:10.1016/j.jsbmb.2016.06.009

Cited by 62 publications

(37 citation statements)

References 63 publications

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“…However, the plasma concentrations of 11OHA-dione, 11KA-dione, 11OHT and 11KT measured by LC-MS/MS are significantly increased in 21-hydroxylase (CYP21A)deficient patients, supporting the hypothesis that these steroids are originating from adrenal precursors (Turcu et al 2016). Interestingly, remarkable levels of 11KT and 11KDHT were also detected in prostate tissue and plasma of prostate cancer (PCa) patients by LC-MS/MS (du Toit et al 2017), suggesting their potential importance in androgen-dependent tumor growth particularly in castration-resistant prostate cancer (CRPC).…”

Section: Detecting Novel Androgenic Ligands With Mass Spectrometric Amentioning

confidence: 86%

Applying mass spectrometric methods to study androgen biosynthesis and metabolism in prostate cancer

Knuuttila

Hämäläinen

Poutanen

2019

Journal of Molecular Endocrinology

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Recent development of gas chromatography and liquid chromatography-tandem mass spectrometry (GC-MS/MS, LC-MS/MS) has provided novel tools to define sex steroid concentrations. These new methods overcome several of the problems associated with immunoassays for sex steroids. With the novel MS-based applications we are now able to measure small concentrations of the steroid hormones reliably and with high accuracy in both body fluids and tissue homogenates. The sensitivity of the tandem mass spectrometry assays allows us also for the first time to reliably measure picomolar or even femtomolar concentrations of estrogens and androgens. Furthermore, due to a high sensitivity and specificity of MS technology, we are also able to measure low concentrations of steroid hormones of interest in the presence of pharmacological concentration of other steroids and structurally closely related compounds. Both of these features are essential for multiple preclinical models for prostate cancer. The MS assays are also valuable for the simultaneous measurement of multiple steroids and their metabolites in small sample volumes in serum and tissue biopsies of prostate cancer patients before and after drug interventions. As a result, novel information about steroid hormone synthesis and metabolic pathways in prostate cancer has been obtained. In our recent studies, we have extensively applied a GC-MS/MS method to study androgen biosynthesis and metabolism in VCaP prostate cancer xenografts in mice. In the present review, we shortly summarize some of the benefits of the GC-MS/MS and novel LC-MS/ MS assays, and provide examples of their use in defining novel mechanisms of androgen action in prostate cancer. Journal of Molecular Endocrinology(2019) 62, R255-R267

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Section: Detecting Novel Androgenic Ligands With Mass Spectrometric Amentioning

confidence: 86%

Applying mass spectrometric methods to study androgen biosynthesis and metabolism in prostate cancer

Knuuttila

Hämäläinen

Poutanen

2019

Journal of Molecular Endocrinology

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“…Notably, 11keto-DHT levels were in the 10-20 nM range before treatment and showed no decrease after ADT, suggesting significant AR activation potential. This is also reflected by prominent tissue levels of these 11-oxygenated C19 steroids (du Toit et al 2017). Until recently, these steroids and their physiological role has been overlooked in the literature and an increasing number of studies now confirm these steroids as interesting targets for androgen-dependent diseases, including PC.…”

Section: Alternative Pathways Of Androgen Synthesismentioning

confidence: 99%

“…It can be produced from androstenedione by CYP11B1, and although this steroid itself does not activate the AR, it can be converted into 11-keto variants of testosterone and DHT that are equally potent agonists of the AR (Swart & Storbeck 2015, Pretorius et al 2016. Plasma levels of 11OH-androstenedione and 11keto-testosterone have recently been investigated and shown to reach a high baseline and augmented post-ADT levels of above 100 nM (du Toit et al 2017). Notably, 11keto-DHT levels were in the 10-20 nM range before treatment and showed no decrease after ADT, suggesting significant AR activation potential.…”

Section: Alternative Pathways Of Androgen Synthesismentioning

confidence: 99%

Circulating steroid hormone variations throughout different stages of prostate cancer

Snaterse¹,

Visser²,

Arlt³

et al. 2017

Endocrine-Related Cancer

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Steroid hormones play a central role in the maintenance and progression of prostate cancer. The androgen receptor is the primary driver of tumor cell proliferation and is activated by the androgens testosterone and 5α-dihydrotestosterone. Inhibition of this pathway through medical or surgical castration improves survival in the majority of advanced prostate cancer patients. However, conversion of adrenal androgen precursors and alternative steroidogenic pathways have been found to contribute to tumor progression and resistance to treatment. The emergence of highly accurate detection methods allows us to study steroidogenic mechanisms in more detail, even after treatment with potent steroidogenic inhibitors such as the CYP17A1 inhibitor abiraterone. A clear overview of steroid hormone levels in patients throughout the local, metastatic and castration-resistant stages of prostate cancer and treatment modalities is key toward a better understanding of their role in tumor progression and treatment resistance. In this review,

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“…Recently, du Toit and colleagues assessed, for the first time, the presence of 11oxC19 steroids in two CRPC tissue samples and in the peripheral serum of other two patients with CRPC. The most abundant C 19 steroid in the prostate tissue of both patients was 11OHA4, while the other steroids demonstrated variable concentrations [37]. In the peripheral serum of the two patients with CRPC studied, concentrations of 11KT and 11KDHT were considerably higher than those of T and DHT, respectively.…”

Section: Castration-resistant Prostate Cancer (Crpc)mentioning

confidence: 99%

“…In an in vitro model provided by two androgen-dependent prostate cancer cell lines (LNCaP and VCaP), 11KT and 11KDHT were metabolized to inactive products significantly more slowly than T and DHT, respectively [39]. Furthermore, du Toit and colleagues showed that while most T was conjugated to T-glucuronide by 48 h in the LNCaP cells, 11KT and 11KDHT were only poorly glucuronidated [37]. These findings suggest that intracellular 11KT and 11KDHT remain available to activate AR longer than T and DHT.…”

Section: Castration-resistant Prostate Cancer (Crpc)mentioning

confidence: 99%

Clinical significance of 11-oxygenated androgens

Turcu

Auchus

2017

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of review The adrenal gland is considered a source of weak androgens, such as dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione. Emerging evidence proposes a set of 11-oxygenated 19-carbon (11oxC19) adrenal-derived steroids as clinically important androgens. Such steroids include: 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone and 11-ketotestosterone. This review will discuss the synthesis, androgenic activity and clinical implications of the 11oxC19 steroids. Recent findings The clinical relevance of the 11oxC19 steroids resides in two key characteristics: 1. the synthesis of all 11oxC19 originates predominantly in the adrenal cortex; and 2. 11-ketotestosterone and its 5α-reduced metabolite, 11-ketodihydrotestosterone are potent agonists of the human androgen receptor, similar to the classic androgens testosterone and dihydrotestosterone, respectively. Recent studies have demonstrated higher than normal circulating levels of 11oxC19 steroids in patients with 21-hydroxylase deficiency and in polycystic ovary syndrome. The 11oxC19 steroids are also thought to contribute to castration-resistant prostate cancer progression. Additionally, the 11oxC19 steroids might have clinical implications in adrenarche and postmenopausal women. Summary Future prospective studies are needed to establish the clinical utility of the 11oxC19 steroids for individualized patient care. Preliminary data suggest that these biomarkers hold promise to improve the evaluation and management of androgen excess disorders.

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Profiling adrenal 11β-hydroxyandrostenedione metabolites in prostate cancer cells, tissue and plasma: UPC2-MS/MS quantification of 11β-hydroxytestosterone, 11keto-testosterone and 11keto-dihydrotestosterone

Cited by 62 publications

References 63 publications

Applying mass spectrometric methods to study androgen biosynthesis and metabolism in prostate cancer

Applying mass spectrometric methods to study androgen biosynthesis and metabolism in prostate cancer

Circulating steroid hormone variations throughout different stages of prostate cancer

Clinical significance of 11-oxygenated androgens

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