Zinc is a potential therapeutic for chemoresistant ovarian cancer.

Ovarian cancer is the leading cause of death from gynecological cancer. The high mortality rate reflets the lack of early diagnosis and limited treatment alternatives. We have observed a number of properties of zinc cytotoxicity that make it attractive from a therapeutic standpoint.

Zinc functions as a cytotoxic agent for prostate cancer cells independent of culture and growth conditions.

The effects of zinc on the viability of PC3, LNCaP and DU145 prostate cancer cell lines in vitro were examined. The data indicate that, despite their distinctly different gene expression profiles, morphology and tissue origin, all cell lines responded to zinc in a similar time and dose dependent manner. Experiments using pyrithione indicated that cell death is mediated by internalized zinc.

Direct intra-tumoral injection of zinc-acetate halts tumor growth in a xenograft model of prostate cancer.

Intracellular levels of zinc have shown a strong inverse correlation to growth and malignancy of prostate cancer. To date, studies of zinc supplementation in prostate cancer have been equivocal and have not accounted for bioavailability of zinc. Therefore, we hypothesized that direct intra-tumoral injection of zinc could impact prostate cancer growth.

Zinc induces ERK-dependent cell death through a specific Ras isoform.

The effect of Zn on p53-independent cell death was examined in IIC9 embryonic fibroblasts. Despite the fact that these cells are p53-minus, Zn-mediated death occurs via an apoptotic mechanism. Death is facilitated by the presence of the Zn ionophore, pyrithione, indicating that intracellular Zn initiates the death response.

Zinc inhibition of adenylyl cyclase correlates with conformational changes in the enzyme.

We have previously demonstrated that Zn(2+) inhibits hormone and forskolin stimulation of cAMP synthesis in intact N18TG2 cells, corresponding plasma membranes, and of recombinant adenylyl cyclase isoforms. If, however, the enzyme is pre-activated by hormone or forskolin, Zn(2+) inhibition is attenuated [J. Biol.

Nitric oxide and the other cyclic nucleotide.

Nitric oxide (NO) participates in the regulation of the daily activities of cells as well as in cytotoxic events. Elucidating the mechanism(s) by which NO carries out its diverse functions has been the goal of numerous laboratories. In the cardiovascular system, evidence indicates that NO mediates its effects via an activation of soluble guanylyl cyclase (sGC).

Zinc inhibition of cAMP signaling.

Zn(2+) is required as either a catalytic or structural component for a large number of enzymes and thus contributes to a variety of important biological processes. We report here that low micromolar concentrations of Zn(2+) inhibited hormone- or forskolin-stimulated cAMP production in N18TG2 neuroblastoma cells. Similarly, low concentrations inhibited hormone- and forskolin-stimulated adenylyl cyclase (AC) activity in membrane preparations and did so primarily by altering the V(max) of the enzyme.