THE INHIBITORY EFFECT OF URSODEOXYCHOLIC ACID AND PENTOXIFYLLINE ON PLATELET-DERIVED GROWTH FACTOR-STIMULATED PROLIFERATION IS DISTINCT FROM AN EFFECT BY CYCLIC-AMP

This study assessed the ability of ursodeoxycholic acid (UDCA) and one of its metabolites, tauroursodeoxycholic acid (TUDCA), to inhibit pla telet derived growth factor (PDGF) stimulated fibroproliferation and c ompared these results to the effect of pentoxifylline and its metaboli te-1 [1-(5-hydroxyhexyl)-3,7-dimethylxanthine] and assessed the potent ial role of cyclic AMP in this process. Fibroproliferative activity wa s measured by the tritiated thymidine uptake assay in human fibroblast cultures. All four compounds: pentoxifylline, metabolite-1, UDCA and TUDCA inhibited the fibroproliferative activity stimulated by PDGF (8 ng/ml). Incubation of fibroblasts with dibutyryl cyclic AMP reduced pr oliferation stimulated by PDGF suggesting that the PDGF stimulated pro liferation was sensitive to inhibition by a membrane permeable analogu e of cyclic AMP. Incubation of myofibroblasts with dibutyryl cyclic AM P significantly inhibited PDGF stimulated proliferation suggesting tha t cyclic AMP can regulate PDGF stimulated proliferation in the myofibr oblast. To determine if the effect of pentoxifylline on fibroprolifera tion was mediated by cyclic AMP, we used dideoxyadenosine, a potent in hibitor of adenylyl cyclase. The effect of pentoxifylline on fibroprol iferation was not prevented by dideoxyadenosine, which inhibits format ion of cyclic AMP, thus suggesting that the inhibitory effect of pento xifylline on PDGF-stimulated proliferation of fibroblasts was not medi ated by cyclic AMP, arguing against a role for cyclic AMP in this proc ess. Combinations of UDCA (250 mu M) plus pentoxifylline (120 mu M) or UDCA (250 mu M) plus TUDCA (250 mu M) inhibited fibroproliferative ac tivity stimulated by PDGF to a greater extent than either drug alone. As UDCA has been reported to decrease cyclic AMP these results argue a gainst a role for cyclic AMP in this process. Finally the results sugg est that UDCA may inhibit PDGF-stimulated proliferation via an inhibit ion of C-kinase. (C) 1998 Elsevier Science B.V. All rights reserved.