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.
Chrzanowski
Krzysztof
K
Department of Medicinal Chemistry, Medical Academy of Białystok, Kilinskiego 1, 15 230 Białystok, Poland.
Bielawska
Anna
A
Bielawski
Krzysztof
K
Pałka
Jerzy
J
Wołczyński
Sławomir
S
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D001241:Aspirin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004150:Dipeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism*
D000970:Antineoplastic Agents; D016861:Cyclooxygenase Inhibitors; D011355:Prodrugs; D004150:Dipeptidases; C022449:proline dipeptidase; D001241:Aspirin