The effect of alpha- and gamma-tocopherol and their carboxyethyl hydroxychroman metabolites on prostate cancer cell proliferation

It is known that γ-tocopherol inhibits human prostate cancer cell proliferation via down-regulation of cyclin-related signalling but tocopherol and tocotrienol metabolites with a shortened phytyl chain, carboxyethyl hydroxychromans, were not previously investigated as anti-proliferative agents. In this study, the effect of the two main tocopherols, namely, α-tocopherol and γ-tocopherol, and their corresponding metabolites (α- and γ-carboxyethyl hydroxychromans) was studied on proliferation and cyclin D1 expression of the prostate cancer cell line PC-3. The hydrosoluble vitamin E analogues Trolox and α-tocopherol succinate were also tested. The most effective inhibitors of PC-3 proliferation were γ-tocopherol and γ-carboxyethyl hydroxychroman. Their effect was discernable at 1 μM and reached a plateau at concentrations ⩾10 μM with maximal inhibition values ranging between 70 and 82%. α-Tocopherol, α-carboxyethyl hydroxychroman, and the analogue Trolox were much less effective; a weak effect was observed for concentrations ⩽10 μM and a maximal inhibition of less than 45% was found at 50 μM concentration. PC-3 cells showed higher inhibition, particularly by the γ derivatives, than HTB-82 and HECV cells. Tocopherols and carboxyethyl hydroxychromans exerted an inhibitory effect on cyclin D1 expression parallel to the retardation of cell growth. γ-Carboxyethyl hydroxychroman and γ-tocopherol showed effects also upstream of the cyclin modulation. Furthermore, the inhibition of cyclin D1 expression by γ-carboxyethyl hydroxychroman was competed for by α-carboxyethyl hydroxychroman. In conclusion, this study shows that carboxyethyl hydroxychroman metabolites are as effective as their vitamin precursors to inhibit PC-3 growth by specific down-regulation of cyclin expression, with the γ forms being the most effective ones. Although the inhibition of PC-3 cell growth and diminution of cyclin expression are clearly visible, more subtle mechanistic effects of tocopherols and their corresponding carboxyethyl hydroxychroman metabolites deserve further investigations.