SK channel activation potentiates auranofin-induced cell death in glio- and neuroblastoma cells

Krabbendam, I. E., Honrath, B., Bothof, L., Silva-Pavez, E., Huerta, H., Peñaranda Fajardo, N. M., Dekker, F., Schmidt, M., Culmsee, C., César Cárdenas, J., Kruyt, F. & Dolga, A. M., 15-Nov-2019, In : Biochemical Pharmacology. 13 p., 113714.

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Brain tumours are among the deadliest tumours being highly resistant to currently available therapies. The proliferative behaviour of gliomas is strongly influenced by ion channel activity. Small-conductance calcium-activated potassium (SK/KCa) channels are a family of ion channels that are associated with cell proliferation and cell survival. A combined treatment of classical anti-cancer agents and pharmacological SK channel modulators has not been addressed yet. We used the gold-derivative auranofin to induce cancer cell death by targeting thioredoxin reductases in combination with CyPPA to activate SK channels in neuro- and glioblastoma cells. Combined treatment with auranofin and CyPPA induced massive mitochondrial damage and potentiated auranofin-induced toxicity in neuroblastoma cells in vitro. In particular, mitochondrial integrity, respiration and associated energy generation were impaired. These findings were recapitulated in patient-derived glioblastoma neurospheres yet not observed in non-cancerous HT22 cells. Taken together, integrating auranofin and SK channel openers to affect mitochondrial health was identified as a promising strategy to increase the effectiveness of anti-cancer agents and potentially overcome resistance.

Original languageEnglish
Article number113714
Number of pages13
JournalBiochemical Pharmacology
Publication statusE-pub ahead of print - 15-Nov-2019

ID: 103411385