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.     

Gallium nitride MEMS resonators: how residual stress impacts design and performances

Microsystem Technologies - Starting from Gallium Nitride epitaxially grown on silicon, pre-stressed micro-resonators with integrated piezoelectric transducers have been designed, fabricated, and...     

Action of nitrogenated and sulfonylated inositol derivatives upon the proliferation in vitro of normal mouse cells and tumor mouse cells

Despite the major advances of cancer chemotherapy during the past 40 years, host toxicities and drug resistance justify the need to continue the search for new antineoplastic agents. In the present work, we have studied the effect of six synthetic drugs on the in vitro growth of two murine mammary adenocarcinomas (M3 and MM3), as well as on normal embryonic cells. AI, MIC and MPI are purines coupled to a sulfonylated inositol, while DIC and DEI have nitrogen mustard as substituent. Methylsulfonylmucoinositol was the common substituent. Our results indicated that only drugs substituted with nitrogen mustards had an antiproliferative effect. DEI was more effective on tumor cells than on normal cells.