Expert opinion on therapeutic targets · 2015
Carbonic anhydrase IX inhibition is an effective strategy for osteosarcoma treatment.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Perut Francesca, Carta Fabrizio, Bonuccelli Gloria, Grisendi Giulia, Di Pompo Gemma, Avnet Sofia, Sbrana Francesca Vittoria, Hosogi Shigekuni, Dominici Massimo, Kusuzaki Katsuyuki, Supuran Claudiu T, Baldini Nicola
Аннотация
OBJECTIVE: Hypoxia-inducible factor 1, a regulator of CA IX activity, is often overexpressed in human osteosarcoma (OS) but not in normal tissues, and its expression levels correlate with prognosis. In this study, we investigated the therapeutic potential of newly synthesized CA IX sulfonamide inhibitors in OS.
METHODS: CA IX expression was evaluated in OS cell lines and bone marrow stromal cells (BMSC). After treatment with CA IX inhibitors, cell proliferation, apoptosis, cell cycle, extracellular and cytosolic pH changes were evaluated both in vitro and in mouse OS xenografts.
RESULTS: CA IX expression levels were significantly higher in OS than in BMSC. Accordingly, CA IX inhibitor 3 induced remarkable cytotoxicity on OS cells without affecting BMSC proliferation. This activity was increased under hypoxia, and was mediated by cell cycle arrest and by the modulation of cytosolic and extracellular pH. In vivo, CA IX inhibitor 3 reduced tumor growth by inducing significant necrosis.
CONCLUSIONS: Our results provide a strong rationale for the clinical use of the newly synthesized CA IX inhibitor 3 in human OS.
METHODS: CA IX expression was evaluated in OS cell lines and bone marrow stromal cells (BMSC). After treatment with CA IX inhibitors, cell proliferation, apoptosis, cell cycle, extracellular and cytosolic pH changes were evaluated both in vitro and in mouse OS xenografts.
RESULTS: CA IX expression levels were significantly higher in OS than in BMSC. Accordingly, CA IX inhibitor 3 induced remarkable cytotoxicity on OS cells without affecting BMSC proliferation. This activity was increased under hypoxia, and was mediated by cell cycle arrest and by the modulation of cytosolic and extracellular pH. In vivo, CA IX inhibitor 3 reduced tumor growth by inducing significant necrosis.
CONCLUSIONS: Our results provide a strong rationale for the clinical use of the newly synthesized CA IX inhibitor 3 in human OS.
Предметные рубрики MeSH
AdolescentAdultAgedAnimalsAntigens, NeoplasmAntineoplastic AgentsApoptosisBone NeoplasmsCarbonic Anhydrase IXCarbonic Anhydrase InhibitorsCarbonic AnhydrasesCell HypoxiaCell Line, TumorCell ProliferationFemaleGene Expression Regulation, NeoplasticHumansHypoxia-Inducible Factor 1MaleMiceMice, Inbred NODOsteosarcomaSulfonamidesTumor Cells, CulturedXenograft Model Antitumor Assays