Proline-linked nitrosoureas as prolidase-convertible prodrugs in human breast cancer cells.
A number of novel proline-linked nitrosoureas (1-4) were synthesized and examined for cytotoxicity and influence on DNA and collagen biosynthesis in MDA-MB-231 and MCF-7 human breast cancer cells. Evaluation of the cytotoxicity of these compounds employing a MTT assay and inhibition of [(3)H]thymidine incorporation into DNA in both MDA-MB-231 and MCF-7 breast cancer cells demonstrated that compound 2, the most active of the series, proved to be only slightly less potent than carmustine. It has also been found that carmustine did not inhibit MCF&-7 cells prolidase activity, while compounds 1-4 significantly increased its activity, when used at 50-250 microM concentrations. Proline-linked nitrosoureas (1-4) also had lower ability to inhibit collagen biosynthesis in MCF-7 cells, compared to carmustine. The expression of beta(1)-integrin receptor and phosphorylated MAPK, ERK(1) and ERK(2) was significantly decreased in MCF-7 cells incubated for 24 h with 60 microM of compounds 2 and 4 compared to the control, untreated cells, whereas under the same conditions carmustine did not evoke any changes in expression of all these signaling proteins, as shown by Western immunoblot analysis. These results indicate the proline-linked nitrosoureas (1-4), represent multifunctional inhibitors of breast cancer cell growth and metabolism.
Bielawski
Krzysztof
K
Department of Medicinal Chemistry and Drug Technology, Medical University of Białystok, Kilińskiego 1, PL 15-089 Białystok, Poland. kbiel@amb.edu.pl
Bielawska
Anna
A
Słodownik
Tomasz
T
Bołkun-Skórnicka
Urszula
U
Muszyńska
Anna
A
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002330:Carmustine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D003094:Collagen / Q000096:biosynthesis; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004150:Dipeptidases / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D007202:Indicators and Reagents; D019012:Integrin beta1 / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D009607:Nitrosourea Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles
D018906:Antineoplastic Agents, Alkylating; D004273:DNA, Neoplasm; D007202:Indicators and Reagents; D019012:Integrin beta1; D009607:Nitrosourea Compounds; D011355:Prodrugs; D013778:Tetrazolium Salts; D013844:Thiazoles; D003094:Collagen; D011392:Proline; D017526:Receptor, IGF Type 1; D020928:Mitogen-Activated Protein Kinases; D004150:Dipeptidases; C022449:proline dipeptidase; C022616:thiazolyl blue; D002330:Carmustine