title: V-ATPase as an effective therapeutic target for sarcomas.
abstract: Malignant tumors show intense glycolysis and, as a consequence, high lactate production and proton efflux activity. We investigated proton dynamics in osteosarcoma, rhabdomyosarcoma, and chondrosarcoma, and evaluated the effects of esomeprazole as a therapeutic agent interfering with tumor acidic microenvironment. All sarcomas were able to survive in an acidic microenvironment (up to 5.9–6.0 pH) and abundant acidic lysosomes were found in all sarcoma subtypes. V-ATPase, a proton pump that acidifies intracellular compartments and transports protons across the plasma membrane, was detected in all cell types with a histotype-specific expression pattern. Esomeprazole administration interfered with proton compartmentalization in acidic organelles and induced a significant dose-dependent toxicity. Among the different histotypes, rhabdomyosarcoma, expressing the highest levels of V-ATPase and whose lysosomes are most acidic, was mostly susceptible to ESOM treatment.
authors.forename: Francesca
authors.initials: F
authors.lastname: Perut
authors.forename: Sofia
authors.initials: S
authors.lastname: Avnet
authors.forename: Caterina
authors.initials: C
authors.lastname: Fotia
authors.forename: Serena Rubina
authors.initials: SR
authors.lastname: Baglìo
authors.forename: Manuela
authors.initials: M
authors.lastname: Salerno
authors.forename: Shigekuni
authors.initials: S
authors.lastname: Hosogi
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kusuzaki
authors.forename: Nicola
authors.initials: N
authors.lastname: Baldini
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D064098:Esomeprazole / Q000494:pharmacology*; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D060888:Real-Time Polymerase Chain Reaction; D012509:Sarcoma / Q000188:drug therapy* / Q000201:enzymology*; D013329:Structure-Activity Relationship; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D025262:Vacuolar Proton-Translocating ATPases; D064098:Esomeprazole