PT - JOURNAL ARTICLE AU - Rosanna Supino AU - Giovanna Petrangolini AU - Graziella Pratesi AU - Monica Tortoreto AU - Enrica Favini AU - Laura Dal Bo AU - Patrizia Casalini AU - Enrico Radaelli AU - Anna Cleta Croce AU - Giovanni Bottiroli AU - Paola Misiano AU - Carlo Farina AU - Franco Zunino TI - Antimetastatic Effect of a Small-Molecule Vacuolar H<sup>+</sup>-ATPase Inhibitor in in Vitro and in Vivo Preclinical Studies AID - 10.1124/jpet.107.128587 DP - 2008 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 15--22 VI - 324 IP - 1 4099 - http://jpet.aspetjournals.org/content/324/1/15.short 4100 - http://jpet.aspetjournals.org/content/324/1/15.full SO - J Pharmacol Exp Ther2008 Jan 01; 324 AB - On the basis of the evidence that vacuolar H+-ATPase is implicated in the development of the metastatic phenotype, we have explored the possibility to target the enzyme function in an attempt to control the metastatic behavior of tumor cells. In this study, we used an indole derivative, NiK-12192 [4-(5,6-dichloro-1H-indol-2-yl)-3-ethoxy-N-(2,2,6,6-tetramethyl-piperidin-4-yl)-benzamide], recently identified as an effective inhibitor of vacuolar H+-ATPase, as a potential antimetastatic agent in the treatment of NSCLC H460 xenograft, which is able to induce lung metastases in mice. Oral administration of NiK-12192 caused a significant inhibition of formation of spontaneous metastases. In contrast, the drug exhibited a negligible effect on the development of artificial metastases (i.e., after i.v. injection of tumor cells), thus supporting that the drug affects the early events of the metastatic process (e.g., migration and invasion). Cellular effects are consistent with this interpretation. In conclusion, the available results show for the first time that a vacuolar H+-ATPase inhibitor is effective in modulation of the metastatic behavior of a lung carcinoma, supporting its potential therapeutic interest as a novel treatment approach. The American Society for Pharmacology and Experimental Therapeutics