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.

Carbonic anhydrase IX inhibition is an effective strategy for osteosarcoma treatment / 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. - In: EXPERT OPINION ON THERAPEUTIC TARGETS. - ISSN 1472-8222. - 19:12(2015), pp. 1593-1605. [10.1517/14728222.2016.1086339]

Carbonic anhydrase IX inhibition is an effective strategy for osteosarcoma treatment

GRISENDI, Giulia;DOMINICI, Massimo;
2015

Abstract

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.
10-set-2015
19
12
1593
1605
Carbonic anhydrase IX inhibition is an effective strategy for osteosarcoma treatment / 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. - In: EXPERT OPINION ON THERAPEUTIC TARGETS. - ISSN 1472-8222. - 19:12(2015), pp. 1593-1605. [10.1517/14728222.2016.1086339]
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
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1082427
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