Proline analogue of melphalan as a prodrug susceptible to the action of prolidase in breast cancer MDA-MB 231 cells.
Proline analogue of melphalan (Mel-pro) was synthesized as a prodrug susceptible to the action of ubiquitously distributed, cytosolic imidodipeptidase-prolidase [E.C.3.4.13.9]. Conjugation of melphalan (Mel) with proline (Pro) through imido-bond resulted in formation of a good substrate for prolidase. Cytosolic location of prolidase in neoplastic cell suggests that proline analogue of melphalan (Mel-pro) may serve as a prolidase convertible prodrug. We have compared several aspects of pharmacologic actions of Mel and Mel-pro in estrogen-independent breast cancer MDA-MB 231 cells. It has been found that Mel-pro is more effectively transported into the MDA-MB 231 cells, evokes higher cytotoxicity, similar inhibitory effect on DNA synthesis, lower inhibitory effect on collagen biosynthesis and reduces IGF-I receptor and MAPkinase expression in MDA-MB 231 cells, compared to Mel. The results suggest that targeting of prolidase as a Mel-pro-converting enzyme may serve as a potential strategy in pharmacotherapy of breast cancer.
Department of Medicinal Chemistry, Medical Academy of Białystok, Kilinskiego 1, 15-230 Białystok, Poland.
Krzysztof
K
Chrzanowski
Anna
A
Bielawska
Jerzy
J
Pałka
D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004150:Dipeptidases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008558:Melphalan / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D011392:Proline / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use
D011355:Prodrugs; D011392:Proline; D004150:Dipeptidases; C022449:proline dipeptidase; D008558:Melphalan