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Abstract 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. In this study, we evaluated the cytotoxic properties of the pH neutral salt zinc acetate on the prostate cancer cell lines PC3, DU145 and LNCaP. Zinc acetate killed prostate cancer cell lines in vitro, independent of androgen sensitivity, in a dose-dependent manner in a range between 200 and 600 μM. Cell death occurred rapidly with 50% cell death by six hours and maximal cell death by 18 hours. We next established a xenograft model of prostate cancer and tested an experimental treatment protocol of direct intra-tumoral injection of zinc acetate. We found that zinc treatments halted the growth of the prostate cancer tumors and substantially extended the survival of the animals, whilst causing no detectable cytoxicity to other tissues. Thus, our studies form a solid proof-of-concept that direct intra-tumoral injection of zinc acetate could be a safe and effective treatment strategy for prostate cancer.

Low concentrations of ADP increase the autophosphorylation rate of Escherichia coli succinyl-coenzyme A synthetase (SCS) while GDP increases the concentration of the phosphoenzyme. ADP has no effect on the total amount of phosphorylated SCS and increases phosphorylation only if ATP, or SCS and P(sub i) are used for the phosphorylation. GDP increases the phosphoenzyme level by inhibiting a suppressor protein and requires the presence of ATP. High concentrations of GDP also increase the SCS phosphorylation instead of decreasing it.

Ovarian cancer is the leading cause of death from gynecological cancer. The high mortality rate reflects 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. Using SK0V3 and ES2 cells, ovarian cancer cell lines that demonstrate varied degrees of resistance to known therapeutics, we show that zinc killing is time and concentration dependent. Death is preceded by distinct changes in cell shape and size. The effects of zinc are additive with cisplatin or doxorubicin, whose morphological effects are distinct from those of zinc. Cytotoxicity of paclitaxel is minimal, making it difficult to determine additivity with zinc. Paclitaxel results in changes in cell shape and size similar to those of zinc but has different effects on cell cycle progression and cyclin expression. The data indicate that the means by which zinc kills ovarian cancer cells is distinct from currently used chemotherapeutics. Based on the properties reported here, zinc has the potential to be developed as either a primary treatment or as a second line of defense against cancers that have developed resistance to currently used chemotherapeutics. [ABSTRACT FROM AUTHOR]

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. Zinc effects on cells plated as monolayers were compared to its effects on cells plated in a collagen matrix. Although the rate of cell growth in the matrix was delayed compared to cells in 2-dimensional cultures, the cytotoxic effects of zinc were unaltered. Using both 2-dimensional and 3-dimensional cultures, we observed that zinc cytotoxicity was independent of both the culture conditions and the rate of cell growth, results that contrast the activity of the current chemotherapeutics used to treat prostate cancer. The attractive properties of zinc cytotoxicity demonstrated in this paper suggest that is can be developed as a novel and effective chemotherapeutic agent for prostate cancer treatment. [ABSTRACT FROM AUTHOR]

The ability of compounds releasing nitric oxide (NO) to regulate glyceraldehyde-3-phosphate dehydrogenase (GraPDH) activity was analysed both in cell homogenates and in intact Dictyostelium discoideum. The time course of GraPDH inactivation in cell lysates by NO-releasing compounds suggests that two processes may be involved, one of which accounts for the majority of the inactivation and shows a close correlation with GraPDH ADP-ribosylation. Maximal ADP-ribosylation under these conditions exhibited a stoichiomelry of about 0.4 mol ADP-ribose/mol enzyme tetramer. NO-mediated inhibition of GraPDH activity was attenuated if specific substrates, cofactors. or cysteine were added to cytosol preparations. Under such conditions. ADP-ribosylation of the enzyme was correspondingly reduced or negligible. Intact cells treated with NO-releasing compounds were shown to respond by rapidly decreasing their GraPDH activity. This inhibition was transient andm, after a l0-min incubation, enzyme activity returned to the level seen in control cells. The time course of these in vivo changes core,elated well with those of the NO-stimulated ADPribosylation of GraPDH also seen in intact cells. The basis underlying the NO-stimulated inhibition of GraPDH activity was investigated and found to reflect a decreased Vmax. No changes in either the Km of the enzyme for its substrates or its state of polymerization were observed. [ABSTRACT FROM AUTHOR]