Antiproliferative Role of Natural and Semi-Synthetic Tocopherols on Colorectal Cancer Cells Overexpressing the Estrogen Receptor β

Estrogen receptor β (ERβ) is the most highly expressed subtype in the colon epithelium and mediates the protective effect of estrogen against the development of colon cancer. Indeed, the expression of this receptor is inversely related to colorectal cancer progression. Structurally estrogen-like compounds, including vitamin E components, affect cell growth by binding to ERs. In the present study, cell proliferation was measured by cell counting in a Bürker hemocytometer, and ERβ expression was measured by Real-Time qPCR and immunoenzymatic methods. The results obtained show that natural δ-tocopherol (<b>δ-Toc</b>) and two of its semi-synthetic derivatives, bis-δ-tocopheryl sulfide <b>(δ-Toc)₂S</b> and bis-δ-tocopheryl disulfide <b>(δ-Toc)₂S₂</b>, play an antiproliferative role and upregulate ERβ expression, similar to 17-β-estradiol (17β-E2), in human colon adenocarcinoma HCT8 cells engineered to overexpress ERβ protein (HCT8-β8). These events are not present in HCT8-pSV2neo and in HCT8-β8 pretreated with ICI 182,780, suggesting that they are mediated by the binding of compounds to ERβ, as also boosted by an in silico assay. The antiproliferative effect is independent of the intracellular redox state and <b>(δ-Toc)₂S</b> and <b>(δ-Toc)₂S₂</b> reduce cell proliferation at concentrations lower than that of <b>δ-Toc</b> and all tested compounds are also able to upregulate ERβ expression. Taken together, the data indicate that, through the involvement of ERβ activity and expression, <b>δ-Toc</b>, <b>(δ-Toc)₂S</b>, and <b>(δ-Toc)₂S₂</b> may provide potential therapeutic support against colorectal cancer.