Pleiotropic drug resistance in cystic fibrosis fibroblasts: increased resistance to cyclic AMP.

In previous studies, cystic fibrosis (CF) fibroblasts were demonstrated to be resistant 
to the cytotoxic effects of ouabain, dexamethasone, and the sex hormones, 
dihydrotestosterone, 17beta- estradiol, and progesterone. We now show that CF fibroblasts 
also exhibit greatly increased resistance to the cytotoxic effects of exogenous 
dibutyryl cyclic AMP (cAMP), as well as to isoproterenol and theophylline, 
drugs which are known to increase endogenous levels of cAMP. CF 
cells were also shown to have normal amounts of (3H)cAMP binding 
to protein kinase as well as normal amounts of cAMP- stimulated 
protein kinase activity. Phosphodiesterase in CF cells was also found to 
be stimulated by cAMP to the same degree as in normal 
cells. These findings suggest that there is no detectable protein kinase 
deficiency in CF cells. cf cells thus appear to be unlike 
some cAMP-resistant mutants described by others which are defective in protein 
kinase activity and cAMP regulation of phosphodiesterase levels. The cross-resistance of 
CF fibroblasts to ouabain, steroid hormones, and cAMP may provide a 
unique opportunity to study the biochemical events involved in the metabolism 
of these drugs as well as the basic biochemical defect in 
a common human genetic disease. 