Antimetastatic effect of a small-molecule vacuolar H+-ATPase inhibitor in in vitro and in vivo preclinical studies.
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.
Supino
Rosanna
R
Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy.
Petrangolini
Giovanna
G
Pratesi
Graziella
G
Tortoreto
Monica
M
Favini
Enrica
E
Bo
Laura Dal
LD
Casalini
Patrizia
P
Radaelli
Enrico
E
Croce
Anna Cleta
AC
Bottiroli
Giovanni
G
Misiano
Paola
P
Farina
Carlo
C
Zunino
Franco
F
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D019772:Topotecan / Q000627:therapeutic use; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C514015:4-(5,6-dichloro-1H-indol-2-yl)-3-ethoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)benzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D039302:Integrin alphaVbeta3; D019772:Topotecan; D025262:Vacuolar Proton-Translocating ATPases