Verapamil inhibits tumor protease production, local invasion and metastasis development in murine carcinoma cells
✍ Scribed by Eduardo F. Farías; Julio A. Aguirre Ghiso; Virginia Ladeda; Elisa Bal de Kier Joffé
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- French
- Weight
- 384 KB
- Volume
- 78
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
The invasion and metastasis process involves degradation of the extracellular matrix mediated by tumor-and hostproduced proteolytic enzymes. The main enzymes involved in this process are urokinase-type plasminogen activator (uPA) and the matrix metalloproteinases (MMPs). Calcium is a main co-factor in the signaling pathways that regulate cell proliferation and protease production. We have studied here the effect of verapamil, a calcium channel blocker widely used to treat hypertensive diseases, on local tumor growth, spontaneous and experimental metastasis development, tumorassociated protease production and circulating MMP activity in tumor-bearing mice. BALB/c mice treated for 45 days with verapamil showed no toxic effects. Oral administration of verapamil to mice injected with F3II tumor cells, either pre-treated or not with verapamil, showed a significant decrease of local tumor invasion and both spontaneous and experimental metastasis development (51.3% inhibition of metastasis in both cases, p F 0.01). uPA and MMP-9 production by tumor cells in vitro was significantly inhibited by verapamil in a dose-dependent manner, showing a long-term inhibition after removal of the drug. Verapamil also exhibited a marked cytostatic effect on F3II cell proliferation in vitro. In addition, circulating MMP activity, usually enhanced in tumorbearing mice, diminished significantly with all verapamil treatments. Our results suggest that modulation of the calcium-dependent signaling pathways that regulate tumoror host-dependent production of proteases and tumor cell proliferation could contribute to the inhibition of metastasis development. Finally, we describe the inhibitory effects of a commonly used hypotensor in humans, verapamil, on the invasive and metastatic capacity of mammary tumor cells.