SK channel activation potentiates auranofin-induced cell death in glio- and neuroblastoma cellsKrabbendam, 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.
Research output: Contribution to journal › Article › Academic › peer-review
- Molecular Pharmacology
- Chemical and Pharmaceutical Biology
- Medicinal Chemistry and Bioanalysis (MCB)
- Biopharmaceuticals, Discovery, Design and Delivery (BDDD)
- Groningen Research Institute for Asthma and COPD (GRIAC)
- Guided Treatment in Optimal Selected Cancer Patients (GUTS)
- Damage and Repair in Cancer Development and Cancer Treatment (DARE)
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.
|Number of pages||13|
|Publication status||E-pub ahead of print - 15-Nov-2019|