Herg K+ Channel-Dependent Apoptosis and Cell Cycle Arrest in Human Glioblastoma Cells

Staudacher, Ingo; Jehle, J; Staudacher, Kathrin; Pledl, Hans-Werner; Lemke, Dieter; Schweizer, Patrick; Becker, Rüdiger; Katus, Hugo A.; Thomas, Dierk

doi:10.1371/journal.pone.0088164

Cited by 47 publications

(44 citation statements)

References 36 publications

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“…Consistent with in vitro and in vivo animal findings in PCa, classical α-antagonists and their analogues appear to have broad activity, exhibiting cytotoxicity in other cancer cell lines including urogenital [44,65,66,67,68,69,70,71,72,73,74], gastrointestinal [73,74,75,76,77], lung [74,78], blood [79], brain [80,81] and thyroid [82]. Importantly, the cytotoxic and anti-proliferative effects are supported by several in vivo mice studies [48,66], suggesting ubiquitous anticancer actions of these drugs.…”

Section: Discussionsupporting

confidence: 53%

The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers

Batty

Pugh

Rathinam

et al. 2016

IJMS

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This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers.

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Section: Discussionsupporting

confidence: 53%

The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers

Batty

Pugh

Rathinam

et al. 2016

IJMS

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“…Therefore, we checked the effect of three compounds, namely Doxazosin, PLX-4720 and Igmesine, which have been shown to alter potassium channel expression at protein level in other systems. Doxazosin is an α1-adrenoceptor antagonist which is able to bind hERG potassium channel (Kv11.1) and to reduce the channel protein level, thereby triggering cell death [24]. B-RAF inhibitor PLX-4720 is a potent anti-proliferative and pro-apoptotic ).…”

Section: Inhibition Of B-raf Pathway Decreases Kv13 Expression In Humentioning

confidence: 99%

Biophysical Characterization and Expression Analysis of Kv1.3 Potassium Channel in Primary Human Leukemic B Cells

Szabó

Trentin

Trimarco

et al. 2015

Cell Physiol Biochem

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Background/Aims: Pharmacological inhibition of the potassium channel Kv1.3 has been shown to selectively kill B cells from patients with chronic lymphocytic leukemia (B-CLL). Here we aimed to biophysically characterize and compare Kv1.3 channel activity in B cells isolated either from healthy subjects or patients and investigated the mechanism accounting for the increased protein expression in B-CLL cells. Methods: Kv1.3 activity was measured by patch clamp, while expression of the channel protein was assessed by Western blot and FACS analysis. B-CLL cells were co-cultured with mesenchymal stromal cells (MSC) and Kv1.3 inhibitor-induced apoptosis was assessed. Results: We demonstrate that Kv1.3 is highly expressed and is more active at resting membrane potential in human B-CLL cells than in healthy cells. Channel expression in pathologic cells decreased by the B-RAF kinase inhibitor PLX-4720, while it increased with Doxazosin, an α1-adrenoceptor antagonist. Kv1.3 inhibitors induced death in B-CLL cells also when co-cultured with MSC. Conclusion: Our results contribute to the characterization of B-CLL cells, as it shows that upregulation of Kv1.3 in pathologic B lymphocytes is linked to the oncogenic B-RAF signalling. We also conclude that Kv1.3 inhibitors represent a valuable tool to induce apoptosis of B-CLL cells even in the presence of MSC.

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“…hERG was shown to be overexpressed in leukemia, gastric cancer, colon cancer and glioblastoma cell lines (8, 12–15). In other tumor cells, altered hERG expression was associated with cell cycle regulation and proliferation (16, 17). Recent work was reported showing a possible role for hERG inhibition in pediatric brain cancer, medulloblastoma (18).…”

Section: Introductionmentioning

confidence: 99%

Administration of Non-Torsadogenic human Ether-à-go-go-Related Gene Inhibitors Is Associated with Better Survival for High hERG–Expressing Glioblastoma Patients

Pointer

Clark

Eliceiri

et al. 2017

Clinical Cancer Research

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Purpose Glioblastoma (GBM) is the most malignant primary brain tumor, with a median survival of less than two years. More effective therapeutic approaches are needed to improve clinical outcomes. Experimental Design Glioblastoma patient-derived cells (GPDCs) were isolated from patient GBMs and implanted in mice to form xenografts. Immunohistochemistry was performed for hERG expression and tumor proliferation. Sphere-forming assays with hERG blocker E-4031 were performed on a highand low hERG expressing lines. A GBM TMA (115 patients) was used to correlate hERG expression with patient survival. Clinical data was analyzed to determine if patient survival was affected by incidental administration of hERG inhibitory drugs, and the correlative effect of patient GBM hERG expression levels. Results hERG expression was upregulated in GBM xenografts with higher proliferative indices. High hERG-expressing GPDCs showed a reduction in sphere formation when treated with hERG inhibitors compared to low hERG-expressing GPDCs. GBM TMA analysis showed worse survival for GBM patients with high hERG expression versus low expression, 43.5 vs. 60.9 weeks respectively (p= 0.022). Furthermore, patients who received at least one hERG blocker had a better survival rate compared to patients who did not (p=0.0015). Subgroup analysis showed that GBM patients with high hERG expression who received hERG blockers had improved survival (p=0.0458). There was no difference in survival for low hERG-expressing GBM patients who received hERG blockers (p=0.4136). Conclusions Our findings suggest that hERG is a potential GBM survival marker, and that already approved drugs with non-torsadogenic hERG inhibitory activity may potentially be re-purposed as adjuvant GBM therapy in high hERG-expressing GBM patients.

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Herg K+ Channel-Dependent Apoptosis and Cell Cycle Arrest in Human Glioblastoma Cells

Cited by 47 publications

References 36 publications

The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers

The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers

Biophysical Characterization and Expression Analysis of Kv1.3 Potassium Channel in Primary Human Leukemic B Cells

Administration of Non-Torsadogenic human Ether-à-go-go-Related Gene Inhibitors Is Associated with Better Survival for High hERG–Expressing Glioblastoma Patients

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