Carbonic anhydrase IX inhibition as a path to treat neuroblastoma

Tumour hypoxia frequently presents a major challenge in the treatment of neuroblastoma (NBL). The neuroblastoma cells produce carbonic anhydrase IX (CA IX), an enzyme crucial for the survival of cancer cells in low-oxygen environments. We designed and synthesised a novel high-affinity inhibitor of C...

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Published in:British journal of pharmacology 2025-01
Main Authors: Petrosiute, Agne, Zakšauskas, Audrius, Lučiūnaitė, Asta, Petrauskas, Vytautas, Baranauskienė, Lina, Kvietkauskaitė, Agnė, Ščerbavičienė, Alvilė, Tamošiūnaitė, Marta, Musvicaitė, Justina, Jankūnaitė, Alberta, Žvinys, Gediminas, Stančaitis, Laimonas, Čapkauskaitė, Edita, Mickevičiūtė, Aurelija, Juozapaitienė, Vaida, Dudutienė, Virginija, Zubrienė, Asta, Grincevičienė, Švitrigailė, Bukelskienė, Virginija, Schiöth, Helgi B, Matulienė, Jurgita, Matulis, Daumantas
Format: Article
Language:English
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Summary:Tumour hypoxia frequently presents a major challenge in the treatment of neuroblastoma (NBL). The neuroblastoma cells produce carbonic anhydrase IX (CA IX), an enzyme crucial for the survival of cancer cells in low-oxygen environments. We designed and synthesised a novel high-affinity inhibitor of CA IX. The highest to-date. The affinities were determined for all human catalytically active CA isozymes showing significant selectivity for CA IX over other isozymes. The inhibitor effect on neuroblastoma cancer cell growth was determined in vitro and in vivo via a mice xenograft model. The novel designed inhibitor effectively mitigated the acidification induced by CA IX and reduced spheroid growth under hypoxic conditions in the SK-N-AS cell line. It also diminished the secretion of pro-tumour chemokines IL-8 (CXCL2) and CCL2. When we combined this novel CA IX inhibitor with a compound that inhibits the chemokine receptor CCR2 protein activity, we observed a reduction in mouse tumour growth. The combined treatment also prompted tumours to exhibit adaptive resistance by producing higher levels of vascular endothelial growth factor receptors (VEGFR) and other compensatory signals. This research underscores the pivotal role of CA IX in cancer and the potential of a novel CA IX inhibitor-based combination intervention therapy for neuroblastoma treatment.
ISSN:0007-1188
1476-5381
1476-5381
DOI:10.1111/bph.17429