To establish a system to study differentiation therapy drugs, we used the androgen-independent human prostate PC-3 tumor cell line as a target and α- and γ-tocopherol as inducers. Effects of α- and γ-tocopherol on the cell cycle, proliferation and differentiation, were examined. A more significant growth inhibition activity for γ- than for α-tocopherol was observed. Flow cytometry analysis of α- and γ-tocopherol-treated prostate carcinoma PC3 cells showed decreased progression into the S-phase. This effect, particularly evident for γ-tocopherol, was associated with an up-regulation and increased activity of transglutaminase 2 (TG2), a reduced DNA synthesis and a remarkable decreased levels of cyclin D1 and cyclin E. Activation of TG2 suggests that γ-tocopherol has an evident differentiative capacity on PC3 cells, leading to an increased expression of TG2, and reduced cyclin D1 and cyclin E levels, affecting cell cycle progression. It is feasible that up-regulation and activation of TG2, associated with a reduced proliferation, are parts of a large-scale reprogramming that can attenuate the malignant phenotype of PC3 cells in vitro. These data suggest further investigation on the potential use of this γ-form of vitamin E as a differentiative agent, in combination with the common cytotoxic treatments for prostate cancer therapy.

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Prostate cancer is the second most common cancer in men worldwide. Its prevention and treatment remain a challenge to clinicians. Thus, there is an urgent need to discover novel, less toxic, and more effective therapies for patients. Many vitamins and related chemicals, including vitamin E, (tocopherols) have shown their anti-cancer activities as anti-oxidants, activators of transcription factors or factors influencing epigenetic events. Although laboratory tests including the use of animal models showed that this vitamin may have anticancer properties, whether it can effectively prevent the development and/or progression of prostate cancer in humans remains to be intensively studied. This review provides up-to-date information regarding the recent outcomes of laboratory, epidemiology and/or clinical trials on the effects of tocopherols on prostate cancer development, along with our last observations on a combined treatment of a prostate cancer cell line (PC-3) with two natural antineoplastic compounds, naringenin (NG) and α-tocopherol (α-TOC). We report the synergic effect of α-TOC and NG in transglutaminase-induced differentiation of human PC-3 prostate cancer cells. While our results are based on one histological class of tumor, the most significant implication of this observation is that establishes a new way in the screening for detecting new differentiative antineoplastic agents.

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