AN INVERSE RELATIONSHIP BETWEEN EXPRESSION OF GST-PI AND DOXORUBICIN RESISTANCE IN A SERIES OF DOXORUBICIN-RESISTANT SUBLINES OF THE NCI-H69 HUMAN SMALL-CELL LUNG-CANCER CELL-LINE

Toxic electrophiles generated in cells upon exposure to doxorubicin have been implicated in the mechanisms of doxorubicin induced cytotoxicity. Glutathione (GSH) and glutathione linked enzymes including glutathione S-transferases, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase are components of a prominent cellular electrophile detoxification system which defends against the deleterious effects of electrophilic toxins. Increases in glutathione levels and in activity of these enzymes have been observed in some doxorubicin resistant malignant cells in culture, but their overall importance in mediating doxorubicin resistance is controversial. We have performed present studies to determine whether GSH levels, activities of GSH-linked detoxification enzymes or the expression of the pi-class glutathione S-transferases are correlated with degree of doxorubicin resistance in doxorubicin-resistant variants of the NCI-H69 human small cell lung cancer cell line. Although glutathione levels and activities of glutathione-reductase and glucose-6-phosphate dehydrogenase were increased in some of the DOX resistant cell lines, we observed no linear correlation between degree of doxorubicin resistance with GSH levels or activities of glutathione peroxidase; glutathione reductase or glucose-6-phosphate dehydrogenase but an inverse relationship was observed between doxorubicin-resistance and GST activity and expression of the pi-class GST isozyme. Results of our studies suggest that 1.) GSH-linked electrophile detoxification system may play a role in some DOX-resistant cells, 2.) that prolonged exposure to low concentration of doxorubicin may result in down-regulation of GST-pi, and 3.) that decreased expression of GST-pi may confer a survival advantage in these cell lines.