Verapamil inhibits tumor protease production, local invasion and metastasis development in murine carcinoma cells.
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 F311 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 F311 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.
Farías
E F
EF
National Council of Scientific and Technical Research (CONICET), Buenos Aires, Argentina. efarias@invrof.fmed.uba.ar
Aguirre Ghiso
J A
JA
Ladeda
V
V
Bal de Kier Joffé
E
E
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism*; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D014700:Verapamil; D010450:Endopeptidases; D014568:Urokinase-Type Plasminogen Activator; D008666:Metalloendopeptidases