EPIDERMAL GROWTH-FACTOR, PHORBOL ESTERS, AND AURINTRICARBOXYLIC ACID ARE SURVIVAL FACTORS FOR MDA-231 CELLS EXPOSED TO ADRIAMYCIN

The ability of epidermal growth factor (EGF), insulinlike growth facto r-1 (IGF-1), insulin, 12-O-tetradecanoylphorbol-13-acetate (TPA), and aurintricarboxylic acid (ATA) to protect the human breast cancer cell line MDA-231 from death induced by the anticancer drug adriamycin was investigated. Cell death was induced in the MDA-231 cells either by a short-time exposure to a high dose of adriamycin (2 mu g.ml(-1).1 h(-1 )) and further culturing in the absence of the drug, or by continuous exposure to a low dose of adriamycin (0.3 mu g/ml). Cell death was eva luated after 48 h of incubation by several techniques (trypan blue dye exclusion, lactic dehydrogenase activity, cellular ATP content, trans mission electron microscopy, and DNA fragmentation). EGF, TPA, and ATA , each at an optimal concentration of 20 ng/ml, 5 ng/ml, and 100 mu g/ ml respectively, substantially enhanced survival of cells exposed eith er to a high or low dose of adriamycin. Neither IGF-1 nor insulin, eac h at concentrations of 20 ng/ml, had an effect on cell survival. The t hree survival factors enhanced protein synthesis in the untreated cell s and attenuated the continuous decrease in protein synthesis in the a driamycin-treated cells. Moreover, the three survival factors protecte d the MDA-231 cells from death in the absence of protein synthesis (cy cloheximide 30 mu g/ml). These results suggest that EGF, TPA, and ATA promote survival of adriamycin pretreated cells by at least two mechan isms: enhancement of protein synthesis and by a protein synthesis inde pendent process, probably a posttranslational modification effect.