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 Calorini

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1341-1353
Number of pages13
JournalJournal of Molecular Medicine
Volume95
Issue number12
DOIs
Publication statusPublished - Dec 1 2017

Fingerprint

Acidosis
Cell Survival
Neoplasms
Carbonic Anhydrase IX
Carbonic Anhydrase Inhibitors
Phenotype
Clinical Trials, Phase I
Epithelial-Mesenchymal Transition
Tumor Microenvironment
Drug Resistance
Colorectal Neoplasms
Melanoma
Cell Death
Clinical Trials
Apoptosis
Breast Neoplasms

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

Andreucci, E., Peppicelli, S., Carta, F., Brisotto, G., Biscontin, E., Ruzzolini, J., ... Calorini, L. (2017). Carbonic anhydrase IX inhibition affects viability of cancer cells adapted to extracellular acidosis. Journal of Molecular Medicine, 95(12), 1341-1353. https://doi.org/10.1007/s00109-017-1590-9

Carbonic anhydrase IX inhibition affects viability of cancer cells adapted to extracellular acidosis. / Andreucci, Elena; Peppicelli, Silvia; Carta, Fabrizio; Brisotto, Giulia; Biscontin, Eva; Ruzzolini, Jessica; Bianchini, Francesca; Biagioni, Alessio; Supuran, Claudiu T.; Calorini, Lido.

In: Journal of Molecular Medicine, Vol. 95, No. 12, 01.12.2017, p. 1341-1353.

Research output: Contribution to journalArticle

Andreucci, E, Peppicelli, S, Carta, F, Brisotto, G, Biscontin, E, Ruzzolini, J, Bianchini, F, Biagioni, A, Supuran, CT & Calorini, L 2017, 'Carbonic anhydrase IX inhibition affects viability of cancer cells adapted to extracellular acidosis', Journal of Molecular Medicine, vol. 95, no. 12, pp. 1341-1353. https://doi.org/10.1007/s00109-017-1590-9
Andreucci, Elena ; Peppicelli, Silvia ; Carta, Fabrizio ; Brisotto, Giulia ; Biscontin, Eva ; Ruzzolini, Jessica ; Bianchini, Francesca ; Biagioni, Alessio ; Supuran, Claudiu T. ; Calorini, Lido. / Carbonic anhydrase IX inhibition affects viability of cancer cells adapted to extracellular acidosis. In: Journal of Molecular Medicine. 2017 ; Vol. 95, No. 12. pp. 1341-1353.
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