Combinatorial treatments of tamoxifen and SM6Met, an extract from Cyclopia subternata Vogel, are superior to either treatment alone in MCF-7 cells

Abstract

Synergistic drug combinations are not only popular in antibiotic, anti-microbial, immune disease (i.e., AIDS) and viral infection studies, but has also gained traction in the field of cancer research as a multi-targeted approach. It has the potential to lower the doses needed of standard of care (SOC) therapeutic agents, whilst maintaining an effective therapeutic level. Lower dosages could ameliorate the fundamental problems such as drug resistance and metastasis associated with current SOC therapies. In the current study, we show that the combination of SM6Met with (2)-4-hydroxytamoxifen (4-OH-Tam, the active metabolite of tamoxifen) produces a strong synergistic effect in terms of inhibiting MCF7 ER-positive (ER+) 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 on its own. Cell cycle analyses of the best combination ratios of SM6Met and 4-OH-Tam also suggests that the combination results in increased accumulation of cells in the S-phase and in the apoptotic phase. Moreover, the best combination ratio (20:1) of SM6Met with 4-OH-Tam displayed greater anti-metastatic potential in terms of inhibiting ER+ breast cancer cell migration, invasion, and colony formation than the SOC therapy 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 ER+ breast cancer metastasis.

Dexamethasone–tamoxifen combination exerts synergistic therapeutic effects in tamoxifen-resistance breast cancer cells

“…Previous studies have found that TAM therapy inhibits migration in MCF-7 cells but not in the resistant TAMR-1 cells [ 78 ]. Furthermore, it was reported that combination treatment leads to a more significant delay in cancer cell migration when compared with TAM monotherapy [ 79 , 80 ]. DEX monotherapy and combination with other anticancer agents such as doxorubicin and docetaxel results in a significant inhibitory effect on BC cell migration [ 81–83 ].…”

Cyclopia extracts act as selective estrogen receptor subtype downregulators in estrogen receptor positive breast cancer cell lines: Comparison to standard of care breast cancer endocrine therapies and a selective estrogen receptor agonist and antagonist

“…longifolia , and C. maculata, demonstrate anti-diabetic ( Chellan et al, 2014 ; Schulze et al, 2016 ), anti-obesity ( Pheiffer et al, 2013 ; Jack et al, 2018 ), and immune-stimulatory activities ( Murakami et al, 2018 ) and osteoclast formation inhibition ( Visagie et al, 2015 ); in addition to their useful application in nutraceutical, and cosmetic products ( Joubert et al, 2019 ). Particularly of relevance to the current study, the C. subternata Vogel extract, SM6Met, was shown in several studies to possess phytoestrogenic activity, to display ERα antagonism and ERβ agonism, to antagonize estrogen-induced proliferation in ER + BC cells ( Mfenyana et al, 2008 ; Louw et al, 2013 ; Visser et al, 2013 ; Mortimer et al, 2015 ; van Dyk, 2018 ) and to ameliorate BC in rats ( Visser et al, 2016 ; Oyenihi et al, 2018 ). Like SM6Met, the cup of tea (CoT) extract from C. subternata Vogel and the C. genistoides extract, P104, also exhibit phytoestrogenic properties and antagonize estrogen-induced proliferation in ER + BC cells ( Verhoog et al, 2007b ; Visser et al, 2013 ; Roza et al, 2017 ).…”