Carbonic anhydrase IX inhibition is an effective strategy for osteosarcoma treatment

Francesca Perut, Fabrizio Carta, Gloria Bonuccelli, Giulia Grisendi, Gemma Di Pompo, Sofia Avnet, Francesca Vittoria Sbrana, Shigekuni Hosogi, Massimo Dominici, Katsuyuki Kusuzaki, Claudiu T. Supuran, Nicola Baldini

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1593-1605
Number of pages13
JournalExpert Opinion on Therapeutic Targets
Volume19
Issue number12
DOIs
Publication statusPublished - Dec 2 2015

Keywords

  • acidosis
  • carbonic anhydrase IX
  • hypoxia
  • osteosarcoma
  • sulfonamide

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Clinical Biochemistry
  • Molecular Medicine

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  • Cite this

    Perut, F., Carta, F., Bonuccelli, G., Grisendi, G., Di Pompo, G., Avnet, S., Sbrana, F. V., Hosogi, S., Dominici, M., Kusuzaki, K., Supuran, C. T., & Baldini, N. (2015). Carbonic anhydrase IX inhibition is an effective strategy for osteosarcoma treatment. Expert Opinion on Therapeutic Targets, 19(12), 1593-1605. https://doi.org/10.1517/14728222.2016.1086339