Decrease of cyclin D1 in the human lung adenocarcinoma cell line A-427 by 7-hydroxycoumarin
Por:
Jiménez-Orozco F.A., López-González J.S., Nieto-Rodriguez A., Velasco-Velázquez M.A., Molina-Guarneros J.A., Mendoza-Patiño N., García-Mondragón M.J., Elizalde-Galvan P., León-Cedeño F., Mandoki J.J.
Publicada:
1 ene 2001
Resumen:
Coumarin in vivo has antitumor activity in various types of cancer. In vitro, coumarin and 7-hydroxycoumarin, its major biotransformation product in humans, inhibit the proliferation of several human tumor cell lines. The molecular mechanisms of these effects are unknown. To gain information about these mechanisms, we studied the effects of coumarin and 7-hydroxycoumarin in the human lung adenocarcinoma cell line A-427 on the inhibition of: (i) cell proliferation; (ii) cell cycle progression; and (iii) expression of cyclins D1, E and A. The inhibitory concentrations 50 (IC50) of both compounds were estimated by cytostatic assays of tetrazolium (MTT) reduction. The effects on cell cycle progression were assayed with propidium iodide and BrdU using DNA histograms and multiparametric flow cytometry. The percentages of cells expressing cyclins D1, E, and A were estimated by means of bivariate flow cytometry using propidium iodide, and FITC-conjugated monoclonal antibodies for each cyclin. The IC50 (± S.E.M. n = 3) of 7-hydroxycoumarin and coumarin at 72 h exposure, were 100 ± 4.8 and 257 ± 8.8 ?g/ml, respectively. 7-Hydroxycoumarin at the concentration of 160 ?g/ml (1 mM), inhibited the G1/S transition of the cell cycle, an action consistent with the cytostatic effect. No significant decreases of cyclins E and A were observed. In contrast, cyclin D1 significantly decreased, which appears to indicate an action of 7-hydroxycoumarin in early events of phase G1. However, messenger RNA of cyclin D1, assayed by RT-PCR, did not change. This suggests a posttranscriptional effect. The effects of coumarin were not significant. Cyclin D1 is overexpressed in many types of cancer, and its inhibition has been proposed as a pharmacological and therapeutic target for novel antitumor agents. Knowledge of the decrease of cyclin D1 by 7-hydroxycoumarin may lead to its use in cancer therapy, as well as to the development of more active compounds. © 2001 Elsevier Science Ireland Ltd. All rights reserved.
Filiaciones:
Jiménez-Orozco F.A.:
Departamento De Farmacología, Facultad De Medicina, Universidad Nacional Autónoma De México, Apdo. Postal 70-297, Mexico D.F. 04510, Mexico
López-González J.S.:
Departamento De Enfermedades Crónico-Degenerativas, Instituto Nacional De Enfermedades Respiratorias, Tlalpan 4502, Col. Seccion XVI, Mexico D.F. 14080, Mexico
Nieto-Rodriguez A.:
Departamento De Enfermedades Crónico-Degenerativas, Instituto Nacional De Enfermedades Respiratorias, Tlalpan 4502, Col. Seccion XVI, Mexico D.F. 14080, Mexico
Velasco-Velázquez M.A.:
Departamento De Farmacología, Facultad De Medicina, Universidad Nacional Autónoma De México, Apdo. Postal 70-297, Mexico D.F. 04510, Mexico
Molina-Guarneros J.A.:
Departamento De Farmacología, Facultad De Medicina, Universidad Nacional Autónoma De México, Apdo. Postal 70-297, Mexico D.F. 04510, Mexico
Mendoza-Patiño N.:
Departamento De Farmacología, Facultad De Medicina, Universidad Nacional Autónoma De México, Apdo. Postal 70-297, Mexico D.F. 04510, Mexico
García-Mondragón M.J.:
Departamento De Farmacología, Facultad De Medicina, Universidad Nacional Autónoma De México, Apdo. Postal 70-297, Mexico D.F. 04510, Mexico
Elizalde-Galvan P.:
Departamento De Química Orgánica, Facultad De Química, Ciudad Universitaria, Mexico D.F. 04510, Mexico
León-Cedeño F.:
Departamento De Química Orgánica, Facultad De Química, Ciudad Universitaria, Mexico D.F. 04510, Mexico
Mandoki J.J.:
Departamento De Farmacología, Facultad De Medicina, Universidad Nacional Autónoma De México, Apdo. Postal 70-297, Mexico D.F. 04510, Mexico
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