Synthetic bile acid derivatives induce nonapoptotic death of human retinalpigment epithelial cells

Purpose. To study whether the synthetic ursodeoxycholic acid (UDCA) and che nodeoxycholic acid (CDCA) derivatives, which we have synthesized and have r eported their apoptosis-inducing effect, have the effect on the proliferati on of retinal pigment epithelial cells. Methods. UDCA, CDCA, and their synthetic derivatives were administered in c ulture to the human retinal pigment cell line, ARPE-19. The effect on cell viability and growth was assessed by trypan blue dye exclusion. In order to evaluate the type of cell death, mitochondrial membrane potential assay, D NA electrophoresis, TUNEL assay, nuclear staining and Western blotting for caspase-3 and poly(ADP-ribose) polymerase (PARP) activities were conducted. Results. Unlike UDCA and CDCA, which did not exhibit a significant effect o n viability, their synthetic derivatives decreased the viability of ARPE-19 cells in a concentration-dependent manner. The cells treated with the synt hetic derivatives did not demonstrate the characteristic findings of apopto sis, such as DNA ladder, DNA fragmentation, nuclear condensation or fragmen tation, and caspase-3 and PARP activation. The reduction of mitochondrial m embrane potential was shown. In electron microscopical study nuclear conden sation was not shown. Conclusions. The synthetic UDCA and CDCA derivatives induced nonapoptotic d eath of ARPE-19 cells.