Inhibitory effect of zinc on human prostatic carcinoma cell growth

BACKGROUND. Normal human prostate accumulates the highest levels of zinc of any soft tissue in the body. In contrast, the zinc level in prostate cance r is markedly decreased from the level detected in nonprostate tissues. Des pite these relationships, the possible role of zinc in the growth of normal and malignant prostate has not been determined. METHODS. Growth inhibition and various regulatory responses were investigat ed in two human prostate carcinoma cell lines (LNCaP and PC-3), treated wit h or without zinc. RESULTS. incubation of the prostate carcinoma cell lines with physiological levels of zinc resulted in the marked inhibition of cell growth. A lower 5 0% inhibition of cell growth (IC50) value for zinc (about 100 ng/ml) was de tected in LNCaP cells, which are androgen-responsive, whereas androgen-inde pendent PC-3 cells exhibited a higher IC50 for zinc (about 700 ng/ml). Incu bation with 1 mu g/ml zinc resulted in maximum inhibition of growth in both cell lines. These inhibitory effects of zinc correlated well with the accu mulation of zinc in the cells. Simultaneously, cell flow cytometric analyse s revealed a dramatic increase of the cell population in G2/M phase, in bot h LNCaP (2.3-fold vs. control) and PC-3 (1.9-fold vs, control), and a decre ased proportion of cells in S phase (LNCaP, -51.4%; PC-3, -23%), indicating a G2/M phase arrest. The cell growth inhibition and G2/M arrest in these c ells were accompanied by an increase in apoptosis, as demonstrated by the c haracteristic cell morphology and further confirmed by cellular DNA fragmen tation. The specificity of zinc-induced apoptosis was identified by ethylen ediamine-tetraacetic acid (EDTA)-chelation, which abolished the zinc effect on cellular DNA fragmentation. The zinc-induced G2/M phase arrest and apop tosis were accompanied by increased mRNA levels of p21(Waf1/Cip1/Sdi1) in b oth LNCaP (p53+/+) and PC-3 (p53-/-) cells. CONCLUSIONS. These results suggest that zinc inhibits human prostatic carci noma cell growth, possibly due to induction of cell cycle arrest and apopto sis. There now exists strong evidence that the loss of a unique capability to retain high levels of zinc is an important factor in the development and progression of malignant prostate cells. (C) 1999 Wiley-Liss, Inc.