Browsing by Author "Van Dyk, Lorinda"

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    Combinatorial treatments of tamoxifen with SM6Met, a selective estrogen receptor subtype modulator (SERSM), from Cyclopia subternata are superior to current endocrine treatments in breast cancer cell models.
    (Stellenbosch : Stellenbosch University, 2018-12) Van Dyk, Lorinda; Louw, Ann; Verhoog, Nicolette J. D.; Stellenbosch University. Faculty of Science. Dept. of Biochemistry.
    ENGLISH ABSTRACT: Globally and in South Africa breast cancer is the most frequent malignancy amongst women. Most breast cancers are estrogen receptor (ER) positive and requires estrogen for growth and metastasis. Adverse side-effects associated with, and resistance to, the current standard of care (SOC) hormone therapies that target estrogen signalling, like tamoxifen, a selective estrogen modulator (SERM), and fulvestrant, a selective estrogen receptor down-regulator (SERD), have driven the recent development of using natural compounds or extracts as novel therapies, either alone or in combination with conventional chemotherapeutic agents, for the treatment and/or prevention of breast cancer. Previous work from our laboratory has suggested that a sequential methanol extract, SM6Met, prepared from the indigenous fynbos plant, Cyclopia subternata (honey bush), has several properties that may make it an effective chemopreventative and/or chemotherapeutic agent for breast cancer. The current study investigated the ability of SM6Met to prevent or treat breast cancer either as monotherapy or in combination with 4-OH-Tam (the active metabolite of tamoxifen) by evaluating its effects on the processes required for the development and progression of breast cancer such as proliferation, migration, invasion and colony formation. Firstly, I validated previous findings, characterizing SM6Met as a selective estrogen receptor subtype modulator (SERSM) that behaves as an ERα antagonist and ERβ agonist, which is able to inhibit estrogen-induced breast cancer cell proliferation. Importantly, I show that although SM6Met as monotherapy could not compete, in terms of efficacy or potency, with current SOC therapies like 4-OH-Tam and fulvestrant, with regard to inhibiting breast cancer cell proliferation, SM6Met showed potential in targeting two pro-metastatic processes, invasion and colony formation, to an extent equal to, if not greater than the SOC therapies and thus has the potential to be developed into a phytoestrogenic nutraceutical that can be beneficial in the prevention and treatment of breast cancer and metastasis. Secondly, I show, for the first time, that the effects of SM6Met could be replicated and enhanced by combining an ERα selective antagonist (MPP) and an ERβ selective agonist (liquiritigenin), thus validating the concept that a treatment with these ideal ER subtype selective properties may be more beneficial for the treatment and prevention of breast cancer and metastasis than current SOC therapies. Thirdly, I show, for the first time, that the combination therapy of 4-OH-Tam and SM6Met produced a strong synergistic effect in terms of antagonizing breast cancer cell proliferation and that a 20 times lower dose of 4-OH-Tam in combination with SM6Met is required to produce the same inhibitory effect on cell proliferation as 4-OH-Tam alone. Moreover, the best combination ratio (20:1) of SM6Met with 4-OH-Tam displayed greater anti-metastatic potential than the extract or the SOC therapies alone, suggesting that SM6Met together with 4-OH-Tam could be a viable drug combination for not only delaying resistance and ameliorating the negative side effects associated with current SOC therapies, like tamoxifen, but could also provide a novel, more affordable therapeutic alternative for treating or preventing breast cancer metastasis.