Browsing by Author "Claassen, Herzelle"

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    Investigating the parts to understand the whole : contribution of phenolic compounds to the desired estrogenic activity of SM6Met fractions from Cyclopia subternata
    (Stellenbosch :Stellenbosch University, 2018-03) Claassen, Herzelle; Louw, Ann; Visser, Koch; Stellenbosch University. Faculty of Science. Dept. of Biochemistry.
    ENGLISH ABSTRACT: Decreasing estrogen levels, associated with menopause, may cause several unpleasant symptoms. Hormone replacement therapy (HRT) relieves these symptoms, but increases the risk of developing breast cancer. As estrogens promote estrogen-receptor positive (ER+) breast cancer, women are seeking alternative forms of hormone therapy and are turning to plant-based products high in phytoestrogens, since they are considered to be a more natural, healthier and potentially safer alternative to HRT. Another alluring aspect of plant-based products are their ability to exert their effect through multiple target mechanisms, which is potentially due to the complex mixture of different bio-active and supporting compounds working together. The current study forms part of a larger ongoing study, which focuses on Cyclopia, an indigenous South African fynbos plant, as a potential nutraceutical to reduce menopausal symptoms, while decreasing the risk of breast cancer. The sequential methanol extract of Cyclopia subternata (SM6Met) displayed promising results in different in vitro and in vivo breast cancer experimental systems, with the desired estrogenic characteristics of ER subtype selectivity, specifically ERβ agonism and ERα antagonism (which is important in ER+ breast cancer since ERα is known to induce proliferation, whereas ERβ antagonises ERα), and the inhibition of estrogen-induced breast cancer cell proliferation. However, the compounds responsible for the desired estrogenic characteristics have not been identified and thus, as a starting point, we focused on the 7 major phenolic compounds quantified in a fraction, F3, obtained from SM6Met. F3 previously displayed robust ERβ agonism, and the aim of the current study was thus to evaluate the combinatorial effect of these 7 major phenolic compounds to the favourable estrogenic profile of F3. Firstly, an experimental system sensitive enough to detect small drug induced changes was successfully established, after which the phytoestrogenic activity of the 7 major phenolic compounds were tested individually and in combination. Interestingly, the reconstituted faction (F3R), in contrast to F3, displayed no significant estrogenic activity when the 7 major phenolic compounds were reconstituted at a concentration equivalent to that which is present in F3. However, when F3R was reconstituted at 100-fold its concentration, a significant increase in activity was observed via both ER subtypes. Mangiferin and luteolin were the only two phenolic compounds that displayed significant and dose-dependent l estrogenic activity when tested alone. Since, at this stage of the study, not much was known regarding the estrogenicity of mangiferin, a more in detailed investigation revealed activity via ERα and also, as a novel finding, via ERβ. The current study concluded that F3’s robust ERβ agonist activity could not be recreated using only the 7 major phenolic compounds at their concentration in F3 but that the minor phenolic compounds play a crucial supporting role in the desired estrogenic profile of this fraction. Thus, the contribution of the 7 major phenolic compounds to F3’s activity, and subsequently the multi target activity of SM6Met, should not be dismissed, since other compounds present in F3, but not in F3R, may act synergistically with the major phenolic compounds to produce the robust ERβ activity of F3.