Acetylsalicylic acid as a potential regulator of prolidase-convertible pro-drugs in control and neoplastic cells.

Proline analogue of melphalan (Mel-pro) is one of the pro-drugs activated by prolidase, cytoplasmic imidodipeptidase highly expressed in some neoplastic tissues. In order to limit the action of prolidase on the pro-drug in normal cells, prolidase inhibitor, acetylsalicylic acid (ASA), was tested in fibroblasts (showing average prolidase activity for normal cells) and in MDA-MB 231 breast cancer cells (showing elevated activity of the enzyme). The effect of Mel-pro in the presence and absence of ASA on prolidase activity (colorimetric assay), DNA biosynthesis (3H-thymidine incorporation assay), cytotoxicity (tetrazoline assay) and ability to penetrate cell membrane (thin layer chromatography) in both type of cells was measured. It has been found that 5 mM ASA significantly decreased conversion of Mel-pro to Mel in cultured fibroblasts as well as it decreased cytotoxicity and the effect of this drug on DNA synthesis. In contrast, 5 mM ASA had relatively lower effect on the conversion of Mel-pro into Mel in MDA-MB 231 cells as well it had little effect on Mel-pro-induced inhibition of DNA synthesis and cell death. It suggests that ASA may serve as an inhibitor of prolidase-convertible pro-drugs in normal cells.