Cytotoxic interactions of Zn2+ in vitro: melanoma cells are more susceptible than melanocytes

Borovanský, J; Blaŝko, M; Siracký, J; Aa, Schothorst; Np, Smit; Pavel, S.

doi:10.1097/00008390-199712000-00002

Cited by 12 publications

(8 citation statements)

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“…The outward current could be due to Zn 2+ efflux through a membrane channel or transporter. Such mechanisms have been described in many systems (Borovansky et al 1997; McMahon & Cousins, 1998) and it was also found that prostate cancer cells (LNCaP and PC‐3) express ZIP1, a Zn 2+ transporter (Franklin et al 2003). In the case of PNT2‐C2 cells, however, the Zn 2+ ‐induced current was delayed and was sensitive to [K + ] o , similar to I cit / I cit/in .…”

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confidence: 92%

Citrate transport in the human prostate epithelial PNT2‐C2 cell line: electrophysiological analyses

Mycielska

Djamgoz

2004

The Journal of Physiology

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Although prostate synthesizes and releases large amounts of citrate, the mechanism of the release is not well understood. Most known citrate transporters mediate uptake of citrate from extracellular space and, consequently, are driven by the transmembrane Na + gradient, which would not be appropriate for prostatic function. In the present study, we investigated citrate transport in a normal human prostate cell line, PNT2-C2, using mainly electrophysiological methods. Intracellular application of citrate through the patch pipette in the whole-cell recording mode induced an outward current whilst in response to extracellular citrate an inward current was recorded. Membrane currents induced by citrate were bigger than those elicited by other (equimolar) Krebs cycle intermediates. Both inward and outward citrate-induced currents had the same ionic dependence, inhibitor profile and reversal potential. In particular, the currents were strongly dependent on the transmembrane K + gradient. Uptake and release of citrate and their K + dependence were confirmed by spectrophotometric enzyme analyses. Citrate-induced membrane currents were also sensitive to pH, consistent with the transporter preferring the trivalent form. Application of intracellular Zn 2+ generated an outward current which had the same quantitative K + dependence as the citrate-induced currents. Extracellular application of a membrane-permeant Zn 2+ chelator generatedaninwardcurrent.Theseexperimentssuggestedthatm-aconitasewastonicallyactive in PNT2-C2 cells. Determination of 'forward' and 'reverse' K + stoichiometry both suggested a citrate : K + ratio of 1 : 4. We conclude that normal prostatic epithelial cells possess an electrogenic citrate transporter which mediates the cotransfer of 1 trivalent citrate anion alongside 4 K + out of cells and thus generates a net outward current.

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confidence: 92%

Citrate transport in the human prostate epithelial PNT2‐C2 cell line: electrophysiological analyses

Mycielska

Djamgoz

2004

The Journal of Physiology

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“…Many metal ions induce oxidative stress in biologic systems, and activate and inhibit a wide range of signaling pathways (37). It has been shown that divalent Zn and Cd salts show toxicity to melanoma at concentrations several orders of magnitude lower than that which affects melanocytes (38,39). The mechanism through which combinations of these factors may influence melanocyte transformation is not well understood.…”

Section: Introductionmentioning

confidence: 99%

Melanosomal Damage in Normal Human Melanocytes Induced by UVB and Metal Uptake—A Basis for the Pro‐oxidant State of Melanoma^†

Gidanian

Mentelle

Meyskens

et al. 2008

Photochem & Photobiology

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Melanins are ubiquitous catecholic pigments, formed in organelles called melanosomes within melanocytes, the function of which is to protect skin against harmful effects of UV radiation. Melanosomes within melanoma cells are characteristically abnormal, with fragmented melanin and disrupted membranes. We hypothesize that the disruption of melanosomal melanin might be an early event in the etiology and progression of melanoma, leading to increased oxidative stress and mutation. In this report, we examine the effect of a combination of UV treatment and metal ion exposure on melanosomes within melanocytes, as well as their ability to act as pro-oxidants in ex situ experiments, and assay the effects of this treatment on viability and cell cycle progression. UVB exposure causes morphologic changes of the cells and bleaching of melanosomes in normal melanocytes, both significantly enhanced in Cu(II) and Cd(II)-treated cells, as observed by microscopy. The promoted bleaching by Cu(II) is due to its ability to redox cycle under oxidative conditions, generating reactive oxygen species; verified by the observed enhancement of hydroxyl radical generation when isolated melanosomes were treated with both Cu(II) ions and UVB, as assayed by DNA clipping. Single-dose UVB/Cu treatment does not greatly affect cell viability or cell cycle progression in heavily pigmented cells, but did so in an amelanotic early stage melanoma cell line.

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“…Melanomas also have unusually high uptake of Cu and other metals, even higher than melanocytes which themselves accumulate metal ions (10). More importantly, melanomas have been shown to be uniquely susceptible to increases of certain divalent metal salts; for instance, Zn(II) and Cd(II) salts induce melanoma death at concentrations several orders of magnitude lower than that which affects melanocytes (11, 12).…”

Section: Introductionmentioning

confidence: 99%

Melanin as a Target for Melanoma Chemotherapy: Pro‐oxidant Effect of Oxygen and Metals on Melanoma Viability

Farmer

Gidanian

Shahandeh

et al. 2003

Pigment Cell Research

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Melanoma cells have a poor ability to mediate oxidative stress, which may be attributed to constitutive abnormalities in their melanosomes. We hypothesize that disorganization of the melanosomes will allow chemical targeting of the melanin within. Chemical studies show that under oxidative conditions, synthetic melanins demonstrate increased metal affinity and a susceptibility to redox cycling with oxygen to form reactive oxygen species. The electron paramagnetic resonance (EPR)-active 5,5¢-dimethyl-pyrollidine N-oxide spin adduct was used to show that binding of divalent Zn or Cu to melanin induces a pro-oxidant response under oxygen, generating superoxide and hydroxyl radicals. A similar pro-oxidant behaviour is seen in melanoma cell lines under external peroxide stress. Melanoma cultures grown under 95% O 2 ⁄5% CO 2 atmospheres show markedly reduced viability as compared with normal melanocytes. Cu-and Zn-dithiocarbamate complexes, which induce passive uptake of the metal ions into cells, show significant antimelanoma activity. The antimelanoma effect of metal-and oxygen-induced stress appears additive rather than synergistic; both treatments are shown to be significantly less toxic to melanocytes.

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Cytotoxic interactions of Zn2+ in vitro: melanoma cells are more susceptible than melanocytes

Cited by 12 publications

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Citrate transport in the human prostate epithelial PNT2‐C2 cell line: electrophysiological analyses

Citrate transport in the human prostate epithelial PNT2‐C2 cell line: electrophysiological analyses

Melanosomal Damage in Normal Human Melanocytes Induced by UVB and Metal Uptake—A Basis for the Pro‐oxidant State of Melanoma^†

Melanin as a Target for Melanoma Chemotherapy: Pro‐oxidant Effect of Oxygen and Metals on Melanoma Viability

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Cytotoxic interactions of Zn2+ in vitro: melanoma cells are more susceptible than melanocytes

Cited by 12 publications

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Citrate transport in the human prostate epithelial PNT2‐C2 cell line: electrophysiological analyses

Citrate transport in the human prostate epithelial PNT2‐C2 cell line: electrophysiological analyses

Melanosomal Damage in Normal Human Melanocytes Induced by UVB and Metal Uptake—A Basis for the Pro‐oxidant State of Melanoma†

Melanin as a Target for Melanoma Chemotherapy: Pro‐oxidant Effect of Oxygen and Metals on Melanoma Viability

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Melanosomal Damage in Normal Human Melanocytes Induced by UVB and Metal Uptake—A Basis for the Pro‐oxidant State of Melanoma^†