British journal of pharmacology · 2025
Carbonic anhydrase IX inhibition as a path to treat neuroblastoma.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
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
Аннотация
BACKGROUND AND PURPOSE: 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.
EXPERIMENTAL APPROACH: 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.
KEY RESULTS: 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.
CONCLUSIONS AND IMPLICATIONS: 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.
EXPERIMENTAL APPROACH: 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.
KEY RESULTS: 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.
CONCLUSIONS AND IMPLICATIONS: 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.