Zinc dyshomeostasis can induce cell death. However, the mechanisms involved have not been fully elucidated in
prostate cancer (PCa) cells, which differ dramatically from normal cells in their
zinc handling ability. Here, we studied the effects of the
ionophore Zn-
pyrithione (ZP) and the
chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (
TPEN). Both compounds induced cell death at micromolar concentrations when incubated with
androgen-dependent (LNCaP),
androgen-independent (PC3, DU145) and
androgen-sensitive (C4-2) PCa cell-lines. Compared to PCa cells, RWPE1 prostate epithelial cells were less sensitive to ZP and more sensitive to
TPEN, but total cellular
zinc levels were changed similarly. ZnSO4 enhanced the toxicity of ZP, but inhibited the effects of
TPEN as expected. The morphological/biochemical responses to ZP and
TPEN differed. ZP decreased
ATP levels and stimulated ERK, AKT and PKC phosphorylation.
DNA laddering was observed only at low doses of ZP but all doses of
TPEN.
TPEN activated
caspase 3/7 and induced PARP-cleavage, DNA-fragmentation, ROS-formation and apoptotic bodies. PKC and ERK-pathway inhibitors, and
antioxidants protected against ZP-induced but not
TPEN-induced death. Inhibitors of
MPTP-opening protected both. Cell death in response to
TPEN (but not ZP) was diminished by a
calpain inhibitor and largely prevented by a
caspase 3 inhibitor. Overall, the results indicated primarily a necrotic cell death for ZP and an apoptotic cell death for
TPEN. The enhanced sensitivity of PCa cells to ZP and the apparent ability of ZP and
TPEN to kill quiescent and rapidly dividing cells in a p53-independent manner suggest that ZP/
TPEN might be used to develop adjunct treatments for PCa.