Phytosterols in Physiological Concentrations Target Multidrug Resistant Cancer Cells

Abstract

Phytosterols have been proposed to act as potent anticancer agents. However the mechanism of their action has not been elucidated yet. Thus, the aim of our study was to determine whether plant sterols and their thermal processing products (in physiological concentration range) could influence the viability of cancer cells and thus could be considered as positive diet complements. Additionally we decided to study potential specificity of those natural compounds against cells showing high multidrug resistance. In this study we show that the cytotoxic effect of β-sitosterol was observed in both, estrogen-dependent and estrogen-independent cells. It was also shown that the β-sitosterol was significantly more cytotoxic in cells with basal ABCB1 expression (MCF7) than in multidrug resistant NCI/ADR-RES. Surprisingly, 5a,6a-epoxysitosterol did not decrease the viability of any investigated cells but on the contrary, it provoked their increased proliferation. It was shown that oxyphytosterols blocked the cell cycle of MCF7 cells in G0/G1 phase while did not affect NCI/ADR-RES cell cycle in physiological concentration range. We also show that PgP activity (responsible for Multidrug Resistance phenomena) is inhibited by β-sitosterol. Thus, the phytosterols are supposed to act at various mechanisms but, what is most interesting, can target cells showing high multidrug resistance potential.

Apoptotic effect of a phytosterol-ingredient and its main phytosterol (β-sitosterol) in human cancer cell lines

“…Globally, these results confirm the apoptotic action of b-sitosterol, in agreement with our own results. Regarding cell cycle distribution, and in contrast to our findings, b-sitosterol (1 and 5 mM) did not induce significant changes in the cell cycle of MCF-7 cells at 24 h (Rubis et al 2010), possibly because of the lower concentrations and shorter incubation times involved.…”

“…Regarding the b-sitosterol standards, the growth inhibition percentages observed at 13 mM for 48 h are within levels recorded in previous studies (29-81%) with b-sitosterol at 16 mM tested between 1 and 5 days of incubation (Awad et al 2007(Awad et al , 2008Rubis et al 2010). On the other hand, it has been observed that b-sitosterol intake is associated to a greater probability of oestrogen receptor-positive (related to MCF-7) than oestrogen receptor-negative tumours, possibly explaining that MCF-7 cells may be more resistant to this compound (Touillaud et al 2005;Grattan 2013).…”

“…The antiproliferative activity of b-sitosterol standards has been studied in breast cancer (MCF-7) (Awad et al 2007(Awad et al , 2008Rubis et al 2010), colon cancer (HT-29, Caco-2 and/or HCT116) (Awad et al 1996(Awad et al , 1998Choi et al 2003;Daly et al 2009;Montserrat-de la Paz et al 2015) and cervical cancer (HeLa) cells (Cheng et al 2015). Likewise, the anticarcinogenic effects of isolated PS from plant extracts have also been evaluated in MCF-7 (Chai et al 2008;Malek et al 2009;Rahman et al 2013;Yaacob et al 2015;Tahsin et al 2017), in HCT116 (Malek et al 2009;Rahman et al 2013) and in HeLa cells (Block et al 2004;Csupor-Loffler et al 2011;Hamdan et al 2011;Han et al 2013).…”

Telomerase downregulation induces proapoptotic genes expression and initializes breast cancer cells apoptosis followed by DNA fragmentation in a cell type dependent manner

“…Cell cycle analysis and apoptosis detection was performed as previously described [19]. Briefly, after treatment with individual siRNAs targeting TERT and TERC subunits, cells were washed with 1 ml of PBS and fixed with 70 % ethanol overnight at −20 °C.…”

7α-Hydroxy-β-Sitosterol fromChisocheton tomentosusInduces Apoptosis via Dysregulation of Cellular Bax/Bcl-2 Ratio and Cell Cycle Arrest by Downregulating ERK1/2 Activation

“…In recent years, researchers have been focusing on the effects of phytosterols toward various cancer cell lines and their implication in multidrug resistance [19–21]. To date, several apoptotic pathways mediated by phytosterols have been proposed in cancer culture models such as the Ras/ERK and the PI3 K/Akt pathway [22–26].…”