Ganser, Katrin and Stransky, Nicolai and Abed, Tayeb and Quintanilla-Martinez, Leticia and Gonzalez-Menendez, Irene and Naumann, Ulrike and Koch, Pierre and Krueger, Marcel and Ruth, Peter and Huber, Stephan M. and Eckert, Franziska (2024) KCa channel targeting impairs DNA repair and invasiveness of patient-derived glioblastoma stem cells in culture and orthotopic mouse xenografts which only in part is predictable by KCa expression levels. INTERNATIONAL JOURNAL OF CANCER, 155 (10). pp. 1886-1901. ISSN 0020-7136, 1097-0215
Full text not available from this repository. (Request a copy)Abstract
Prognosis of glioblastoma patients is still poor despite multimodal therapy. The highly brain-infiltrating growth in concert with a pronounced therapy resistance particularly of mesenchymal glioblastoma stem-like cells (GSCs) has been proposed to contribute to therapy failure. Recently, we have shown that a mesenchymal-to-proneural mRNA signature of patient derived GSC-enriched (pGSC) cultures associates with in vitro radioresistance and gel invasion. Importantly, this pGSC mRNA signature is prognostic for patients' tumor recurrence pattern and overall survival. Two mesenchymal markers of the mRNA signature encode for IKCa and BKCa Ca2+-activated K+ channels. Therefore, we analyzed here the effect of IKCa- and BKCa-targeting concomitant to (fractionated) irradiation on radioresistance and glioblastoma spreading in pGSC cultures and in pGSC-derived orthotopic xenograft glioma mouse models. To this end, in vitro gel invasion, clonogenic survival, in vitro and in vivo residual DNA double strand breaks (DSBs), tumor growth, and brain invasion were assessed in the dependence on tumor irradiation and K+ channel targeting. As a result, the IKCa- and BKCa-blocker TRAM-34 and paxilline, respectively, increased number of residual DSBs and (numerically) decreased clonogenic survival in some but not in all IKCa- and BKCa-expressing pGSC cultures, respectively. In addition, BKCa- but not IKCa-blockade slowed-down gel invasion in vitro. Moreover, systemic administration of TRAM-34 or paxilline concomitant to fractionated tumor irradiation increased in the xenograft model(s) residual number of DSBs and attenuated glioblastoma brain invasion and (numerically) tumor growth. We conclude, that K-Ca-blockade concomitant to fractionated radiotherapy might be a promising new strategy in glioblastoma therapy.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | POTASSIUM CHANNELS; INHIBITION; ACTIVATION; REQUIRES; PROGRESSION; MIGRATION; K(CA)3.1; SUBTYPES; DISEASE; KCA3.1; DNA damage response; glioma; ionizing radiation; orthotopic xenograft mouse model; potassium channels |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 16 Jan 2026 07:01 |
| Last Modified: | 16 Jan 2026 07:01 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65273 |
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