Vitamin E and other antioxidants inhibit human prostate cancer cells through apoptosis

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Abstract
BACKGROUND Many human prostate cancer cells have escaped the apoptotic effects of natural regulators of cell growth such as transforming growth factor βl (TGF β‐1) and tumor necrosis factor (TNF). METHODS Prostate cancer cell growth was investigated by treating with antioxidants. DU‐145 (androgen‐unresponsive), LNCaP (androgen‐responsive), and ALVA‐101 (androgen moderately responsive) were grown in RPMI‐1640 medium supplemented with bovine fetal calf serum and antibiotics, and were treated with various antioxidants for 1–7 days. Cell growth was then determined with the Cell Titer 96 AQ assay, and apoptosis was assessed by cell death detection ELISA, nuclear morphology, and TUNEL techniques. RESULTS Cells treated with or without (±)‐α‐tocopherol (vitamin E) for 1–7 days at concentrations from 0.078–2.5 μg/ml modestly affected cell growth compared to other antioxidants tested. Tocopherol produced a significant (P < 0.01) inhibition of ALVA‐101 and LNCaP (10–24% of control; 0.078–2.5 μg/ml; at 6 days; n = 6). DU‐145 cells were not growth‐inhibited significantly. However, pyrrolidinedithiocarbamate (PDTC) produced a significant (P < 0.01, n = 6; 17–80% of control; 2.5–20 μg/ml; 1–7 days) inhibition of DU‐145 and ALVA‐101 cells. A significant (P < 0.01) and maximum inhibition of LNCaP cells occurred at all concentration of PDTC (2.5–20 μg/ml). A third compound, diethyldithiocarbamic acid (DETC), incubated for 1–7 days, produced a significant dose response suppression of cell growth of DU‐145 and ALVA‐101 cells (P < 0.01; 14–88% of control; 1.25–80 μg/ml; n = 6). LNCaP cells were inhibited by DETC (P < 0.01; 28% of control; 1.25–80 μg/ml; n = 6). All three antioxidants tested stimulated apoptosis in actively dividing ALVA‐101, DU‐145, and LNCaP cells (P < 0.01; n = 6), but confluent cells were affected less. Testosterone had additive inhibitory effects when combined with PDTC in ALVA‐101 cells; however, the other cell lines were not influenced. CONCLUSIONS These results demonstrate that antioxidants modulate human prostate cancer cell proliferation by altering apoptosis in dividing cells, and this necrosis or apoptosis in confluent cells is not as effective. Prostate 44:287–295, 2000.