Abstract
The aim of this study was to evaluate the cytotoxicity of a series of seven 4′-methylthio-trans-stilbene derivatives against cancer cells: MCF7 and A431 in comparison with non-tumorigenic MCF12A and HaCaT cells. The mechanism of anti-proliferative activity of the most cytotoxic trans-resveratrol analogs: 3,4,5-trimethoxy-4′-methylthio-trans-stilbene (3,4,5-MTS) and 2,4,5-trimethoxy-4′-methylthio-trans-stilbene (2,4,5-MTS) was analyzed and compared with the effect of trans-resveratrol. All the compounds that were studied exerted a stronger cytotoxic effect than trans-resveratrol did. MCF7 cells were the most sensitive to the cytotoxic effect of trans-resveratrol analogs with IC50 in the range of 2.1–6.0 µM. Comparing the cytotoxicity of 3,4,5-MTS and 2,4,5-MTS, a significantly higher cytotoxic activity of these compounds against MCF7 versus MCF12A was observed, whereas no significant difference was observed in cytotoxicity against A431 and HaCaT. In the series of 4′-methylthio-trans-stilbenes, 3,4,5-MTS and 2,4,5-MTS were the most promising compounds for further mechanistic studies. The proapoptotic activity of 3,4,5-MTS and 2,4,5-MTS, estimated with the use of annexin-V/propidium iodide assay, was comparable to that of trans-resveratrol. An analysis of cell cycle distribution showed a significant increase in the percentage of apoptotic cells and G2/M phase arrest in MCF7 and A431 as a result of treatment with 3,4,5-MTS, whereas trans-resveratrol tended to increase the percentage of cells in S phase, particularly in epithelial breast cells MCF12A and MCF7. Both trans-stilbene derivatives enhanced potently tubulin polymerization in a dose-dependent manner with sulfur atom participating in the interactions with critical residues of the paclitaxel binding site of β-tubulin.
Highlights
The aim of this study was to evaluate the cytotoxicity of a series of seven 40-methylthio-transstilbene derivatives against cancer cells: MCF7 and A431 in comparison with non-tumorigenic MCF12A and HaCaT cells
To resveratrol, 2,4,5MTS reduced the viability of cancer cells (MCF7, A431) to a greater extent than their non-tumorigenic counterpart cells (MCF12A and HaCaT)
We investigated the cytotoxic effect of resveratrol and its methylthio-derivatives with the use of cell lines derived from breast epithelium, non-tumorigenic MCF12A and tumorigenic MCF7 and two cell lines derived from human skin epidermis, spontaneously immortalized HaCaT
Summary
The aim of this study was to evaluate the cytotoxicity of a series of seven 40-methylthio-transstilbene derivatives against cancer cells: MCF7 and A431 in comparison with non-tumorigenic MCF12A and HaCaT cells. An analysis of cell cycle distribution showed a significant increase in the percentage of apoptotic cells and G2/M phase arrest in MCF7 and A431 as a result of treatment with 3,4,5-MTS, whereas trans-resveratrol tended to increase the percentage of cells in S phase, in epithelial breast cells MCF12A and MCF7. Resveratrol (3,40,5-trihydroxy-trans-stilbene), a naturally occurring phytoalexin, is the most extensively studied stilbene derivative This compound has been shown to exert several beneficial effects, including cancer chemopreventive activity (Athar et al 2009; Vang et al 2011; Varoni et al 2016; Jiang et al 2017). Induction of cell cycle arrest is considered a rational strategy to turn tumor cells into apoptotic death (Schwarz and Shah 2005)
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