Influence of Rooibos on androgen metabolism in normal and cancer prostate cells – Prof Amanda Swart
Prof Amanda Swart
Title of the project
The influence of Rooibos on androgen metabolism in normal and cancer prostate cells.
In the prostate, androgens regulate cell growth and homeostasis, and play a central role in prostate cancer development. Androgens regulate growth by binding the androgen receptor (AR).The most potent active androgen reported to date, dihydrotestosterone (DHT) which is synthesized from testosterone (T), is closely linked to prostate cancer.
Limiting the production of DHT is a major target in the treatment of prostate cancer as prostate cancer and benign prostatic hyperplasia (BPH) are both androgen dependent. Treatment includes inhibitors of androgen (T and DHT) production and anti-androgens which prevent DHT and other androgens from binding to the AR. Suppressing androgen production has been shown to lead to clinical improvement and lowered prostate specific antigen (PSA) plasma levels. Increased PSA, a protein which liquefies the semen, is a well established prostate cancer biomarker. Prostate cancer screening using serum PSA has led to increased detection of early-stage prostate cancer. PSA is produced in both prostate cancer and BPH, in which the AR linked target genes (such as PSA) are activated.
The majority of patients treated with androgen deprivation therapies present with androgen-independent prostate cancer at a later stage, characterized by high AR expression levels, resuming the expression of multiple genes, which include PSA. Furthermore, the intraprostatic androgen levels in castrated men with androgen-independent prostate cancer are not significantly reduced when compared to men with normal prostate function, indicating that other steroids may be involved in the production of DHT or other steroids may be binding to the AR.
Castration-resistant prostate cancer (CRPC) is dependent upon the generation of DHT with the adrenal gland supplying steroids, dehydroepiandrosterone (DHEA), androstenedione (A4), 11hydroxyandrostenedione (11OHA4) as well as T. In the prostate enzymes,17β-hydroxysteroid dehydrogenase/ketosteroid (17β-HSD) and 5α-reductase (SRD5A) convert androgens to DHT. Steroids produced by the adrenal have been linked to tumor proliferation in CRPC as well as playing a role in BPH. The adrenal steroids are often referred to as adrenal androgens, although these steroids, DHEA, A4 and 11OHA4, have little androgenic activity. Since CRPC is dependent upon the generation of DHT, the precursor steroids, DHEA A4 and 11OHA4 that are supplied by the adrenal gland become important role players in the production of DHT and other active androgens.
Goal 1: The aim of this goal is to determine whether Rooibos inhibits the enzymes which are present in the adrenal gland and responsible for the production of adrenal androgens. We have published data showing that Rooibos inhibits enzymes in the androgen production pathway, thus affecting androgen production in human adrenal cells. We are currently doing experiments in which we assay the inhibition of Rooibos and aspalathin (a flavanoid and anti-oxidant) on three enzymes also in the pathway responsible for the production of A4, 11OHA4 and 11OHT.
Goal 2: The aim of this goal is to determine whether Rooibos inhibits the enzymes which are present in the prostate and are responsible for the production of active androgens (e.g. the production of DHT from T) which can bind to the receptor.
We are in the process of conducting experiments assaying the inhibition by Rooibos and aspalathin of enzymes which are found in normal and cancer prostate cells as well as in BPH cells. Inhibitory assays will be completed in the second half of 2013.
Goal 3: The aim of this goal is to determine whether Rooibos influences the way in which the enzymes present in prostate cells produce active androgens which can bind to the receptor and switch on genes initiating cell proliferation. We will also determine if Rooibos influences (perhaps by enhancing) elimination of these active steroids. We have not started these assays.
We are currently optimizing cell growth conditions (with and without steroids) which will allow us to investigate the effect of Rooibos on growth in normal prostate cells, BPH and cancer cells. The effect of Rooibos will be compared to enzyme inhibitors which are currently used in cancer treatment regimes. Goal 4: The aim of this goal is to determine whether Rooibos can inhibit the formation of active androgens and lower the levels of PSA in cancer cells and in BPH cells. We will be determining the levels of PSA in the presence of and without Rooibos and aspalathin. We have not started these assays.
- Amanda C. Swart, Lindie Schloms, Karl-Heinz Storbeck, Liezl M. Bloem, Therina du Toit, Jonathan L. Quanson, William E. Rainey, Pieter Swart. 11β-Hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11 β -hydroxy-5α-androstanedione. Journal of Steroid Biochemistry & Molecular Biology 138 (2013) 132– 142.
- Karl-Heinz Storbeck, Liezl M. Bloem, Donita Africander, Lindie Schloms, Pieter Swart, Amanda C. Swart. 11 β -Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: A putative role in castration resistant prostate cancer? Molecular and Cellular Endocrinology 377 (2013) 135–146.