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Verapamil inhibits tumor protease production, local invasion and metastasis development in murine carcinoma cells
Author(s) -
Farías Eduardo F.,
Aguirre Ghiso Julio A.,
Ladeda Virginia,
Bal de Kier Joffé Elisa
Publication year - 1998
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19981209)78:6<727::aid-ijc10>3.0.co;2-a
Subject(s) - verapamil , metastasis , cancer research , matrix metalloproteinase , proteases , biology , tumor progression , pharmacology , medicine , calcium , cancer , enzyme , biochemistry
The invasion and metastasis process involves degradation of the extracellular matrix mediated by tumor‐ and host‐produced 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, tumor‐associated 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 < 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 tumor‐bearing mice, diminished significantly with all verapamil treatments. Our results suggest that modulation of the calcium‐dependent signaling pathways that regulate tumor‐ or 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. Int. J. Cancer 78:727–734, 1998. © 1998 Wiley‐Liss, Inc.