Ionizing radiation, ion transports, and radioresistance of cancer cells

Huber, Stephan M.; Butz, Lena; Stegen, Benjamin; Klumpp, Dominik; Braun, Norbert; Ruth, Peter; Eckert, Franziska

doi:10.3389/fphys.2013.00212

Cited by 57 publications

(46 citation statements)

References 164 publications

(203 reference statements)

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“…[15][16][17]. The data of the present study on glioblastoma cell lines and on an ectopic mouse model suggest that IK channels may confer radioresistance besides promoting brain infiltration.…”

Section: Discussionmentioning

confidence: 53%

“…15,16). Like BK, IK channels have been demonstrated to essentially contribute to the mechanics of seruminduced (34), bradykinin-induced (6), and CXCL12 (SDF-1)-induced glioblastoma cell migration (35).…”

Section: Discussionmentioning

confidence: 99%

“…[15][16][17]. Remarkably, the fungicide clotrimazole has been shown to impair glioblastoma growth in vitro and in vivo (18,19) and to promote apoptotic cell death of irradiated glioblastoma cells in vitro (20).…”

Section: Introductionmentioning

confidence: 99%

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Ca2+-Activated IK K+ Channel Blockade Radiosensitizes Glioblastoma Cells

Stegen

Butz

Klumpp

et al. 2015

Molecular Cancer Research

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Ca 2þ -activated K þ channels, such as BK and IK channels, have been proposed to fulfill pivotal functions in neoplastic transformation, malignant progression, and brain infiltration of glioblastoma cells. Here, the ionizing radiation (IR) effect of IK K þ channel targeting was tested in human glioblastoma cells. IK channels were inhibited pharmacologically by TRAM-34 or genetically by knockdown, cells were irradiated with 6 MV photons and IK channel activity, Ca 2þ signaling, cell cycling, residual doublestrand breaks, and clonogenic survival were determined. In addition, the radiosensitizing effect of TRAM-34 was analyzed in vivo in ectopic tumors. Moreover, The Cancer Genome Atlas (TCGA) was queried to expose the dependence of IK mRNA abundance on overall survival (OS) of patients with glioma. Results indicate that radiation increased the activity of IK channels, modified Ca 2þ signaling, and induced a G 2 -M cell-cycle arrest. TRAM-34 decreased the IR-induced accumulation in G 2 -M arrest and increased the number of gH2AX foci post-IR, suggesting that TRAM-34 mediated an increase of residual DNA double-strand breaks. Mechanistically, IK knockdown abolished the TRAM-34 effects indicating the IK specificity of TRAM-34. Finally, TRAM-34 radiosensitized ectopic glioblastoma in vivo and high IK mRNA abundance associated with shorter patient OS in low-grade glioma and glioblastoma.Implications: Together, these data support a cell-cycle regulatory function for IK K þ channels, and combined therapy using IK channel targeting and radiation is a new strategy for anti-glioblastoma therapy. Mol Cancer Res; 13(9); 1283-95. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

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Ca2+-Activated IK K+ Channel Blockade Radiosensitizes Glioblastoma Cells

Stegen

Butz

Klumpp

et al. 2015

Molecular Cancer Research

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“…Electrosignaling has been demonstrated to contribute to neoplastic transformation, malignant progression and therapy resistance of cancer cells (for review see [57]). In glioblastoma cells, radiation has been shown to induce electrosignaling (for review see [58]) that involves Ca 2+ -activated BK K + channels promoting radiogenic hypermigration [37, 38] and Ca 2+ -activated IK K + channels conferring radioresistance [35, 59] in particular in mesenchymal glioblastoma stem cells [60]. While having no effect on radioresistance in the present study, VPA (750 µM) elicited Ca 2+ signals in U251 and U-87MG cells that were paralleled by phosphorylation/degradation of the phosphatase cdc25A (a regulator of G 1 /S transition and S progression [61]) and stabilization of the phosphorylated, inactive form of the mitose promoting factor cdc2.…”

Section: Discussionmentioning

confidence: 99%

Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma

Eckert

Klumpp

Huber

2017

Cell Physiol Biochem

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Background/Aims: Valproic acid (VPA), an anticonvulsant and mood-stabilizing drug is used to treat epileptic seizure of glioblastoma patients. Besides its antiepileptic activity, VPA has been attributed further functions that improve the clinical outcome of glioblastoma patients. Those comprise the inhibition of some histone deacetylase (HDAC) isoforms which reportedly may result in radiosensitization. Retrospective analysis of patient data, however, could not unequivocally confirm a prolonged survival of glioblastoma patients receiving VPA. The present study aimed to identify potential VPA targets at the cellular level. Methods: To this end, the effect of VPA on metabolism, Ca²⁺-, biochemical and electro-signaling, cell-cycling, clonogenic survival and transfilter migration was analyzed in three human glioblastoma lines (T98G, U-87MG, U251) by MTT assay, Ca²⁺ imaging, immunoblotting, patch-clamp recording, flow cytometry, delayed plating colony formation and modified Boyden chamber assays, respectively. In addition, the effect of VPA on clonogenic survival of primary glioblastoma spheroid cultures treated with temozolomide and fractionated radiation was assessed by limited dilution assay. Results: In 2 of 3 glioblastoma lines, clinical relevant concentrations of VPA slightly slowed down cell cycle progression and decreased clonogenic survival. Furthermore, VPA induced Ca²⁺ signaling which was accompanied by pronounced K⁺ channel activity and transfilter cell migration. VPA did not affect metabolic NAD(P)H formation or radioresistance of the glioblastoma lines. Finally, VPA did not impair clonogenic survival or radioresistance of temozolomide-treated primary spheroid cultures. Conclusions: Combined, our in vitro data do not propose a general use of VPA as a radiosensitizer in anti-glioblastoma therapy.

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“…All experiments were performed 12-fold and repeated independently three times. Survival curves were fitted with the linear quadratic model [17].…”

Section: Methodsmentioning

confidence: 99%