title: Carbonic anhydrase IX inhibition is an effective strategy for osteosarcoma treatment.
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.
authors.affiliation: a 1 Istituto Ortopedico Rizzoli, Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine , via di Barbiano 1/10, 40136 Bologna, Italy +39 05 16 36 66 78 ; +39 05 16 36 68 97 ; francesca.perut@ior.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Perut
authors.affiliation: b 2 University of Florence, Section of Pharmaceutical Chemistry, NEUROFARBA Department , Sesto Fiorentino, FI, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.affiliation: a 1 Istituto Ortopedico Rizzoli, Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine , via di Barbiano 1/10, 40136 Bologna, Italy +39 05 16 36 66 78 ; +39 05 16 36 68 97 ; francesca.perut@ior.it.
authors.forename: Gloria
authors.initials: G
authors.lastname: Bonuccelli
authors.affiliation: c 3 University of Modena e Reggio Emilia, Department of Medical and Surgical Sciences for Children & Adults , Modena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Grisendi
authors.affiliation: a 1 Istituto Ortopedico Rizzoli, Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine , via di Barbiano 1/10, 40136 Bologna, Italy +39 05 16 36 66 78 ; +39 05 16 36 68 97 ; francesca.perut@ior.it.
authors.forename: Gemma
authors.initials: G
authors.lastname: Di Pompo
authors.affiliation: a 1 Istituto Ortopedico Rizzoli, Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine , via di Barbiano 1/10, 40136 Bologna, Italy +39 05 16 36 66 78 ; +39 05 16 36 68 97 ; francesca.perut@ior.it.
authors.forename: Sofia
authors.initials: S
authors.lastname: Avnet
authors.affiliation: a 1 Istituto Ortopedico Rizzoli, Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine , via di Barbiano 1/10, 40136 Bologna, Italy +39 05 16 36 66 78 ; +39 05 16 36 68 97 ; francesca.perut@ior.it.
authors.forename: Francesca Vittoria
authors.initials: FV
authors.lastname: Sbrana
authors.affiliation: a 1 Istituto Ortopedico Rizzoli, Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine , via di Barbiano 1/10, 40136 Bologna, Italy +39 05 16 36 66 78 ; +39 05 16 36 68 97 ; francesca.perut@ior.it.
authors.forename: Shigekuni
authors.initials: S
authors.lastname: Hosogi
authors.affiliation: c 3 University of Modena e Reggio Emilia, Department of Medical and Surgical Sciences for Children & Adults , Modena, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Dominici
authors.affiliation: d 4 Kyoto Kujo Hospital, Department of Orthopaedic Surgery , Kyoto, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kusuzaki
authors.affiliation: b 2 University of Florence, Section of Pharmaceutical Chemistry, NEUROFARBA Department , Sesto Fiorentino, FI, Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: a 1 Istituto Ortopedico Rizzoli, Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine , via di Barbiano 1/10, 40136 Bologna, Italy +39 05 16 36 66 78 ; +39 05 16 36 68 97 ; francesca.perut@ior.it.|e 5 University of Bologna, Department of Biomedical and Neuromotor Sciences , Bologna, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Baldini
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000951:Antigens, Neoplasm / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000187:drug effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; D051793:Hypoxia-Inducible Factor 1; D013449:Sulfonamides; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases
keywords: acidosis; carbonic anhydrase IX; hypoxia; osteosarcoma; sulfonamide