title: Effect of a novel vacuolar-H+-ATPase inhibitor on cell and tumor response to camptothecins.
abstract: The vacuolar-H(+)-ATPase, functionally expressed in cell membranes, is known to play a relevant role in intracellular pH regulatory mechanisms, because it is implicated in pumping protons into the extracellular environment or in sequestrating excess protons into acidic vacuolar compartments. Because tumor cells exist in a hypoxic microenvironment and produce acidic metabolites, this regulatory mechanism is recognized as a protective function. This study was designed to investigate the effect of NiK-12192 [4-(5,6-dichloro-1H-indol-2-yl)-3-ethoxy-N-(2,2,6,6-tetramethyl-piperidin-4-yl)-benzamide], an indole derivative identified as an effective inhibitor of vacuolar-H(+)-ATPase, on the cytotoxic activity of two camptothecins, i.e., topotecan and SN-38 (7-ethyl-10-hydroxycamptothecin, the active metabolite of irinotecan). The cellular studies performed in two pairs of human colon carcinoma cell lines, i.e., LoVo and LoVo/DX (overexpressing P-glycoprotein) and HT29 and HT29/Mit (overexpressing breast cancer resistant protein), indicated an enhancement of the antiproliferative effect of camptothecins by concomitant exposure to subtoxic concentrations of NiK-12192. Studies of subcellular distribution indicated that whereas topotecan alone localized mainly in mitochondria and endoplasmic compartment, the simultaneous presence of NiK-12192 caused a cytoplasmic redistribution. In HT29/Mit cells, NiK-12192 reverted the pattern of acidification induced by topotecan. The potentiation of topotecan efficacy by NiK-12192 was documented by an increased efficacy of the combination in both the HT29 tumor xenografts, being more evident in the topotecan-resistant HT29/Mit tumor. In conclusion, the vacuolar-H(+)-ATPase inhibitor NiK-12192 was able to potentiate the cytotoxic/antitumor effects of camptothecins, either in in vitro or in in vivo systems. Such findings support a potential interest for the use of vacuolar-H(+)-ATPase inhibitors in combination therapy to improve camptothecin efficacy.
authors.affiliation: Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Petrangolini
authors.forename: Rosanna
authors.initials: R
authors.lastname: Supino
authors.forename: Graziella
authors.initials: G
authors.lastname: Pratesi
authors.forename: Laura
authors.initials: L
authors.lastname: Dal Bo
authors.forename: Monica
authors.initials: M
authors.lastname: Tortoreto
authors.forename: Anna Cleta
authors.initials: AC
authors.lastname: Croce
authors.forename: Paola
authors.initials: P
authors.lastname: Misiano
authors.forename: Pietro
authors.initials: P
authors.lastname: Belfiore
authors.forename: Carlo
authors.initials: C
authors.lastname: Farina
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000032:analysis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D000077146:Irinotecan; D051379:Mice; D009363:Neoplasm Proteins / Q000032:analysis; D009374:Neoplasms, Experimental / Q000188:drug therapy; D013194:Staining and Labeling; D019772:Topotecan / Q000493:pharmacokinetics / Q000494:pharmacology*; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors*
chemical_list: C514015:4-(5,6-dichloro-1H-indol-2-yl)-3-ethoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)benzamide; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D007211:Indoles; D009363:Neoplasm Proteins; D000077146:Irinotecan; D019772:Topotecan; D025262:Vacuolar Proton-Translocating ATPases; D002166:Camptothecin