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 ha ve been implicated in the mechanisms of doxorubicin induced cytotoxici ty. Glutathione (GSH) and glutathione linked enzymes including glutath ione S-transferases, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase are components of a prominent cellu lar electrophile detoxification system which defends against the delet erious effects of electrophilic toxins. Increases in glutathione level s and in activity of these enzymes have been observed in some doxorubi cin resistant malignant cells in culture, but their overall importance in mediating doxorubicin resistance is controversial. We have perform ed present studies to determine whether GSH levels, activities of GSH- linked detoxification enzymes or the expression of the pi-class glutat hione S-transferases are correlated with degree of doxorubicin resista nce in doxorubicin-resistant variants of the NCI-H69 human small cell lung cancer cell line. Although glutathione levels and activities of g lutathione-reductase and glucose-6-phosphate dehydrogenase were increa sed in some of the DOX resistant cell lines, we observed no linear cor relation between degree of doxorubicin resistance with GSH levels or a ctivities of glutathione peroxidase; glutathione reductase or glucose- 6-phosphate dehydrogenase but an inverse relationship was observed bet ween 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-resista nt cells, 2.) that prolonged exposure to low concentration of doxorubi cin may result in down-regulation of GST-pi, and 3.) that decreased ex pression of GST-pi may confer a survival advantage in these cell lines .