ABSTRACT
BACKGROUND: Zinc supplementation may be beneficial for health. Assessing exchangeable zinc pools may be a useful approach to evaluate zinc status. OBJECTIVE: We evaluated the effects of long-term supplementation with 2 moderate doses of zinc on the mass of exchangeable zinc pools. DESIGN: Three groups of healthy, late-middle-aged men (n = 16 per group) participated in a stable-isotope zinc kinetic study after 6 mo of daily supplementation with 0 (placebo), 15, or 30 mg Zn. At the end of the supplementation period, each subject received an intravenous injection of 0.89 mg (70)Zn, and the plasma zinc disappearance curve was monitored for the next 10 d. Two approaches were used to determine the characteristics of the exchangeable zinc pools: 1) formal 3-compartmental modeling and 2) a simplified determination of the total mass of the rapidly exchangeable zinc pool (EZP). RESULTS: In the placebo group, the exchangeable zinc pool masses for the 3 considered pools were as follows: 2.15, 12.7, and 100.5 mg Zn. The rapidly exchangeable zinc pool mass in the placebo group was 143 mg Zn. Zinc supplementation significantly increased the exchangeable zinc pool masses regardless of the approach used to determine these pools. In addition, these data confirm that exchangeable zinc pool masses correlate positively with total zinc intake and negatively with subject age and do not correlate with plasma zinc concentrations. CONCLUSION: Our data show that long-term supplementation with 2 moderate doses of zinc is an efficient way to increase exchangeable zinc pool masses in late-middle-aged men.
Subject(s)
Zinc/metabolism , Aged , Dietary Supplements , Dose-Response Relationship, Drug , Double-Blind Method , Half-Life , Humans , Male , Middle Aged , Nutritional Status , Zinc/administration & dosage , Zinc/pharmacokineticsABSTRACT
The aim of this study was to investigate the effect of adriamycin (ADR) in signaling activation of NF-kappaB in ADR-sensitive and -resistant GLC(4) human small-cell lung carcinoma. ADR activated NF-kappaB only in ADR-sensitive GLC(4) cells in a time- and dose-dependant manner by stimulating IkappaBalpha degradation after 4h. Activation of NF-kappaB in response to tumor necrosis factor was intact in both cell lines. Topoisomerase II, a target for a number of chemotherapeutic agents, was depleted in both types of GLC(4) cells after ADR treatment, suggesting the stabilization of transient DNA-topoisomerase II complexes. Another transcription factor, Sp1, was activated by ADR, demonstrating the nonspecificity of NF-kappaB activation in ADR-sensitive GLC(4) cells. These findings indicated that resistance to ADR in ADR-sensitive GLC(4) cells did not involve the NF-kappaB transcription factor.
Subject(s)
Doxorubicin/pharmacology , I-kappa B Proteins/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , NF-kappa B/metabolism , Antigens, Neoplasm , Antineoplastic Agents/pharmacology , Base Sequence , Carcinoma, Small Cell/drug therapy , Carcinoma, Small Cell/genetics , Carcinoma, Small Cell/metabolism , Caspase 3 , Caspases/metabolism , DNA/genetics , DNA Topoisomerases, Type II/metabolism , DNA-Binding Proteins , Drug Resistance, Neoplasm , Humans , Lung Neoplasms/genetics , NF-KappaB Inhibitor alpha , NF-kappa B/genetics , Signal Transduction/drug effects , Tumor Cells, CulturedABSTRACT
Anthracyclines are included in clinical treatments against various malignancies, but severe cardiotoxic side-effects and the development of resistance mechanisms limit their usefulness. Many aspects of the cellular response to anthracyclines remain debated. The status of the main regulator of iron homeostasis, namely the RNA-binding activity of iron regulatory proteins (IRPs), has been assessed herein for two types of human tumor cells and their derived doxorubicin-resistant sublines. IRPs were always fully activated in the latter, whereas only partial activation occurred in the former. Doxorubicin exposure reversibly inactivated IRP1 in small cell lung carcinoma (GLC(4)) and myelogenous leukemia (K562) cell lines, but was without effect in their derived doxorubicin-resistant sublines. In contrast, adding doxorubicin to cytosolic fractions of untreated cells or to purified IRPs led to the irreversible alteration of the RNA-binding activity of IRP1. In these different conditions, interaction between doxorubicin and the iron regulatory system disturbs iron metabolism, and cells having developed a resistance mechanism are tuned to maximize the iron supply. The results reported herein may lead the path toward a better therapeutic management of cancer patients receiving doxorubicin by discriminating between the antiproliferative and cardiotoxic properties of this anthracycline.
