Effects of ketoconazole on the proliferation and cell cycle of human cancer cell lines.
The growth-inhibitory effects of ketoconazole, an antifungal agent which inhibits arachidonic acid lipoxygenases and cytochrome P-450 enzymes, were tested in human colon and breast cancer cell lines. In the serum independent HT29-S-B6 colon cell clone, ketoconazole reduced cell proliferation and [3H]thymidine incorporation in a dose-dependent fashion, with a 50% inhibitory concentration of approximately 2.5 microM. Flow cytometry showed an accumulation of cells in the G0-G1 phase of the cell cycle and a concomitant decrease of the percentage of cells in S phase. Ketoconazole also inhibited [3H]thymidine incorporation in the hormone-independent breast cancer cells MDA-MB-231 and Evsa-T, with respective 50% inhibitory concentration of approximately 13 and 2 microM. The mechanism of action of ketoconazole is unknown. However, another lipoxygenase inhibitor, BW755C, inhibited only weakly [3H]-thymidine incorporation and accumulated the cells in S and G2. Conversely, clotrimazole and SKF525A, inhibitors of cytochrome P-450 enzymes, had effects similar to those of ketoconazole on HT29-S-B6 cells whereas metronidazole and secnidazole, other azole derivatives which do not inhibit cytochrome P-450 enzymes, had no effect. The results suggest that cytochrome P-450 enzyme(s) activity(ies) could be implicated in the antiproliferative effects of ketoconazole.
Forgue-Lafitte
M E
ME
Institut National de la Santé et de la Recherche Médicale, INSERM U 55, Centre de Recherches Paris-Saint-Antoine, Hôpital Saint-Antoine, Paris, France.
Coudray
A M
AM
Fagot
D
D
Mester
J
J
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000494:pharmacology; D000230:Adenocarcinoma / Q000473:pathology*; D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003022:Clotrimazole / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000473:pathology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D009376:Neoplasms, Hormone-Dependent / Q000473:pathology*; D014407:Tumor Cells, Cultured
D065607:Cytochrome P-450 Enzyme Inhibitors; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D003022:Clotrimazole; D007654:Ketoconazole