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Journal of Molecular Medicine

, Volume 95, Issue 12, pp 1341–1353 | Cite as

Carbonic anhydrase IX inhibition affects viability of cancer cells adapted to extracellular acidosis

  • Elena Andreucci
  • Silvia Peppicelli
  • Fabrizio Carta
  • Giulia Brisotto
  • Eva Biscontin
  • Jessica Ruzzolini
  • Francesca Bianchini
  • Alessio Biagioni
  • Claudiu T. Supuran
  • Lido CaloriniEmail author
Original Article

Abstract

Among the players of the adaptive response of cancer cells able to promote a resistant and aggressive phenotype, carbonic anhydrase IX (CAIX) recently has emerged as one of the most relevant drug targets. Indeed, CAIX targeting has received a lot of interest, and selective inhibitors are currently under clinical trials. Hypoxia has been identified as the master inductor of CAIX, but, to date, very few is known about the influence that another important characteristic of tumor microenvironment, i.e., extracellular acidosis, exerts on CAIX expression and activity. In the last decades, acidic microenvironment has been associated with aggressive tumor phenotype endowed with epithelial-to-mesenchymal transition (EMT) profile, high invasive and migratory ability, apoptosis, and drug resistance. We demonstrated that melanoma, breast, and colorectal cancer cells transiently and chronically exposed to acidified medium (pH 6.7 ± 0.1) showed a significantly increased CAIX expression compared to those grown in standard conditions (pH 7.4 ± 0.1). Moreover, we observed that the CAIX inhibitor FC16-670A (also named SLC-0111, which just successfully ended phase I clinical trials) not only prevents such increased expression under acidosis but also promotes apoptotic and necrotic programs only in acidified cancer cells. Thus, CAIX could represent a selective target of acidic cancer cells and FC16-670A inhibitor as a useful tool to affect this aggressive subpopulation characterized by conventional therapy escape.

Key messages

  • Cancer cells overexpress CAIX under transient and chronic extracellular acidosis.

  • Acidosis-induced CAIX overexpression is NF-κB mediated and HIF-1α independent.

  • FC16-670A prevents CAIX overexpression and induces acidified cancer cell death.

Keywords

Acidosis of tumor microenvironment Carbonic anhydrase IX (CAIX) FC16-670A CAIX inhibitor Apoptosis 

Notes

Acknowledgements

This study was financially supported by grants from Istituto Toscano Tumori.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Elena Andreucci
    • 1
    • 2
  • Silvia Peppicelli
    • 1
    • 2
  • Fabrizio Carta
    • 3
  • Giulia Brisotto
    • 4
    • 5
    • 6
  • Eva Biscontin
    • 6
  • Jessica Ruzzolini
    • 1
  • Francesca Bianchini
    • 1
    • 2
  • Alessio Biagioni
    • 7
  • Claudiu T. Supuran
    • 3
  • Lido Calorini
    • 1
    • 2
    • 8
    Email author
  1. 1.Department of Clinical and Experimental Biomedical Sciences “Mario Serio”University of FlorenceFlorenceItaly
  2. 2.Istituto Toscano Tumori (ITT)FlorenceItaly
  3. 3.Department of NEUROFARBAUniversity of FlorenceFlorenceItaly
  4. 4.DISCOG, University of PadovaPadovaItaly
  5. 5.Immunology and Molecular Oncology UnitIOV-IRCCSPadovaItaly
  6. 6.Immunopathology and Cancer Biomarkers, Traslational Research DepartmentIRCCS, C.R.O. National Cancer InstitutePordenoneItaly
  7. 7.Department of Surgery and Translational MedicineUniversity of FlorenceFlorenceItaly
  8. 8.Excellence Centre for Research, Transfer and High Education DENOTHEFlorenceItaly

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