Cerivastatin demonstrates enhanced antitumor activity against human breast cancer cell lines when used in combination with doxorubicin or cisplatin.
Competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase are commonly used in the clinic to treat hypercholesterolemia and have been reported to exert antitumor effects. Cerivastatin is a novel, synthetic and the most pharmacologically potent inhibitor of HMG-CoA reductase. We decided to examine the cytostatic/cytotoxic activity of cerivastatin against human breast cancer cell lines and to test whether the effects of cerivastatin could be potentiated by doxorubicin and cisplatin. Cytostatic/cytotoxic effects of cerivastatin used alone or in the combination with chemotherapeutics were measured with MTT assay. The cell cycle distribution and apoptosis induction were evaluated with flow cytometer. The expression of p21 and p27 cyclin-dependent kinase inhibitors was measured with Western blotting. Isobologram analysis was performed to study the drug interactions. We observed that cerivastatin exerts cytostatic/cytotoxic effects against four human tumor cell lines (T-47D, T4-2, MDA-MB-231, MCF-7). We also demonstrated that cerivastatin exerts growth inhibitory effect through induction of p21 cyclin-dependent kinase inhibitor and inhibition of cell cycle progression. In the two tumor cell lines studied, one sensitive (MDA-MB-231) and one moderately resistant (T4-2) to the cytostatic/cytotoxic effects of cerivastatin we examined the effects of combined treatment with cerivastatin and either doxorubicin or cisplatin. Cerivastatin potentiated cytostatic/cytotoxic effects of cisplatin against T4-2 cells and those of doxorubicin against both cell lines. In T4-2 cells the interaction between doxorubicin and cerivastatin and between cisplatin and cerivastatin was found to be synergistic. Altogether, these studies indicate that cerivastatin is another HMG-CoA reductase inhibitor with potent antitumor effects.
Kozar
Katarzyna
K
Department of Immunology, Center of Biostructure Research, 02-004 Warsaw, Poland.
Kaminski
Rafal
R
Legat
Magdalena
M
Kopec
Maciej
M
Nowis
Dominika
D
Skierski
Janusz S
JS
Koronkiewicz
Miroslawa
M
Jakóbisiak
Marek
M
Golab
Jakub
J
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage; D004347:Drug Interactions; D004357:Drug Synergism; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D002352:Carrier Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004317:Doxorubicin; C086276:cerivastatin; D002945:Cisplatin