Decreased sensitivity to adriamycin in cadmium-resistant human lung carcinoma A549 cells

doi:10.1016/S0006-2952(96)00811-8

Biochemical Pharmacology

Volume 53, Issue 5, 7 March 1997, Pages 747-754

https://doi.org/10.1016/S0006-2952(96)00811-8 Get rights and content

Abstract

Cross-resistance presents an obstacle in cancer chemotherapy. Cadmium is a potential carcinogen whose exposure has been shown in epidemiological and laboratory experiments to cause lung cancer. Cadmium also induces various forms of resistance in human lung carcinoma cells. This resistance may be shared by antineoplastic agents, which should be a concern for chemotherapy of cadmium-induced lung cancer. In the present study, two subpopulations of human lung carcinoma A549 cells with a different magnitude of resistance to cadmium coxicity were shown to have a parallel resistance to the cytotoxic action of Adriamycin (ADR), an important anticancer drug. Several factors were examined to investigate the mechanism(s) for the cross-resistance, including cellular metallothionein and glutathione (GSH) concentrations, glutathione S-transferase activity, mdr1 expression, and antioxidant enzyme activities including superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. Only cellular GSH content was elevated consistently in the cadmium/ADR-resistant cells relative to the cadmium/ADR-sensitive cells. Treatment with buthionine sulfoximine, a specific inhibitor of GSH synthesis sensitized both cell lines to ADR only when the cellular GSH levels were depleted to about 5% of control. This BSO treatment, however, did not affect cell viability. Further study revealed that the cadmium/ADR-resistant cells have a greater capacity in recovery of cellular GSH content following BSO treatment. The results demonstrate that cross-resistance to ADR exists in cadmium-resistant human lung carcinoma A549 cells, and enhanced GSH synthesis capacity, rather than elevated levels of cellular GSH, may be related to this resistance.

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Citation Excerpt :
Therefore it was assumed that the increase in toxicity might be an accompanied effect of the diminished glutathione synthesis capability after BSO treatment (BSO a covalently binding substrate to gluCYS-synthetase; (Meister, 1991)), whereat glucocorticoids seem to decrease glutathione content (Rahman et al., 1998), but they do not seem to change glutathione synthesis capability (Walther, 2004). A glutathione synthesis dependent toxicity, but not glutathione content dependent toxicity, was found by Hatcher and coworkers for cadmium toxicity in the A549 cells (Hatcher et al., 1997). They too used BSO to lower cellular glutathione synthesis and glutathione content.
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The human A549 lung cell line is used in this study as a model to evaluate chromium toxicity and mutagenesis since inhalation exposure of this metal gives rise to an epidemiology that indicates the lung as a target organ of chromium toxicity. Hexavalent chromium is considered the carcinogenic form of chromium, however it must be reductively activated following uptake into cells in order to react with intracellular constituents. We have previously established that the fluorescent dyes, dichlorofluorescein (DCF) and dihydrorhodamine, are effective indicators of the reductive activation of chromium and are sensitive measures of the formation of highly reactive chromium species (RCS) intracellularly. In order to examine the role of the two common intracellular reductants, glutathione and ascorbic acid (Vitamin C) in generating RCS intracellularly, we manipulated their intracellular levels through the use of buthionine sulfoximine (BSO) or by the addition of ascorbate into the culture media. We found that the high levels of glutathione in this cancer cell line lowered endogenous oxidation levels markedly, and that, by decreasing intracellular glutathione, BSO not only generated a higher background level of endogenous intracellular oxidation but the chromium-stimulated oxidation also increased markedly. Contrary to it appellation as an anti-oxidant, ascorbic acid stimulated a strong pro-oxidant response upon chromium treatment and this pro-oxidant response was evident regardless of the levels of glutathione in the cells. Based on these results, we conclude that ascorbic acid acts as a pro-oxidant in chromium-treated cells.
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Research paperDecreased sensitivity to adriamycin in cadmium-resistant human lung carcinoma A549 cells

Abstract

J Biol Chem

Free Radic Biol Med

Anal Biochem

Anal Biochem

Methods Enzymol

Anal Biochem

Methods Enzymol

Anal Biochem

Toxicol Lett

Toxicology

Biochem Pharmacol

Time course of MDR gene amplification during in vivo selection for doxorubicin-resistance and during reversal in murine leukemia L 1210

Anticancer Res

Potentiation and protection of doxorubicin cytotoxicity by cellular glutathione and modulation

Cancer Treat Rep

Potentiation of doxorubicin cytotoxicity by buthionine sulfoximine in multidrug-resistant human breast tumor cells

Cancer Res

Doxo-rubicin-induced lipid peroxidation and glutathione peroxidase activity in tumor cells selected for resistance to doxorubicin

Eur J Biochem

Toxic effects of metals

Glutathione a first line of defense against cadmium toxicity

FASEB J

Glutathione is involved in the early cadmium cytotoxic response in human lung carcinoma cells

Toxicology

Research paper
Decreased sensitivity to adriamycin in cadmium-resistant human lung carcinoma A549 cells