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

• Published in: Biochemical pharmacology Vol. 53; no. 5; pp. 747 - 754
• Main Authors: Hatcher, Emiko L., Alexander, Judith M., Kang, Y.James
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 07.03.1997; Elsevier Science
• Subjects: A549 cells; Adriamycin; Antibiotics, Antineoplastic - pharmacology; Antineoplastic agents; Biological and medical sciences; Buthionine Sulfoximine - pharmacology; Cadmium - toxicity; cadmium-resistance; Carcinogens, Environmental - toxicity; cross-resistance; Doxorubicin - pharmacology; Drug Resistance; General aspects; glutathione; Glutathione - analysis; Humans; Lung Neoplasms - chemically induced; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Medical sciences; Pharmacology. Drug treatments; Tumor Cells, Cultured; cadmium-resistance; cross-resistance; A549 cells; Adriamycin; glutathione; Antineoplastic agent; Human; Lung disease; Cadmium; Carcinoma; Respiratory disease; Enzyme; Toxicity; Transferases; Cytotoxicity; Malignant tumor; Doxorubicin; In vitro; Biological activity; Bronchopulmonary; Carcinogen; Glutathione transferase; Multiple resistance; Established cell line; Bronchus disease; Anthracyclins; Cross resistance; Tumor cell; Glutathione
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(96)00811-8

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.