The effect of α- and γ-tocopherol and their carboxyethyl hydroxychroman metabolites on prostate cancer cell proliferation

It is known that gamma-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, alpha-tocopherol and gamma-tocopherol, and their corresponding metabolites (alpha- and gamma-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 alpha-tocopherol succinate were also tested. The most effective inhibitors of PC-3 proliferation were gamma-tocopherol and gamma-carboxyethyl hydroxychroman. Their effect was discernable at 1 M and reached a plateau at concentrations greater than or equal to 10 muM with maximal inhibition values ranging between 70 and 82%. alpha-Tocopherol, alpha-carboxyethyl hydroxychroman, and the analogue Trolox were much less effective; a weak effect was observed for concentrations, less than or equal to10 M and a maximal inhibition of less than 45% was found at 50 muM concentration. PC-3 cells showed higher inhibition, particularly by the gamma 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. gamma-Carboxyethyl hydroxychroman and gamma-tocopherol showed effects also upstream of the cyclin modulation. Furthermore, the inhibition of cyclin D1 expression by gamma-carboxyethyl hydroxychroman was competed for by cc-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 gamma 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. (C) 2003 Elsevier Inc. All rights reserved.