hERG1 Potassium Channels: Novel Biomarkers in Human Solid Cancers

Lastraioli, Elena; Lottini, Tiziano; Bencini, Lapo; Bernini, Marco; Arcangeli, Annarosa

doi:10.1155/2015/896432

Cited by 41 publications

(36 citation statements)

References 60 publications

(81 reference statements)

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“…Although since the current study was performed with a tissue microarray of GBM patients treated before the current standard of adjuvant temozomolide chemoradiation, and markers such as MGMT methylation and IDH mutation status were not known, we are working to confirm our findings with an updated GBM TMA. Other researchers have discussed the role of hERG as a novel biomarker for several other cancers and our work further supports this approach in GBM (32, 33). If validated, hERG expression may be used in the future to stratify GBM patients for possibly hERG inhibitor adjuvant therapy.…”

Section: Discussionsupporting

confidence: 82%

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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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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Section: Discussionsupporting

confidence: 82%

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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Clark

Eliceiri

et al. 2017

Clinical Cancer Research

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“…hERG1 channels were selected as biomarker based on increasing scientific evidence that indicates that aberrant hERG1 expression may be exploited for therapy purposes. 31,43,54,78 Major limitation of hERG1-based tumor therapy in humans is the potential cardiotoxicity that many hERG1 blockers exert. However, a promising first-in-class compound to attempt oncologic therapy without cardiotoxicity, based on targeting the Kv11.1 subunit of the hERG1 channel, has been recently reported, 79 thus supporting the targeting strategy exploited in our study.…”

Section: Discussionmentioning

confidence: 99%

“…hERG1 K + channels are overexpressed in several types of human cancers, 31,54 including PDAC. 43 Anti-Kv11.1-pAb molecules were immobilized on the surface of activated nanoparticles through the formation of amide links between the COOH groups decorating the surface of the PEG-AuNPs and the NH 2 groups of the pAb (Figure 3).…”

Section: Active Targetingmentioning

confidence: 99%

“…The anti-Kv11.1-pAb specifically recognizes surface biomarkers (namely human ether-à-go-go related gene 1 [hERG1] K + channels) aberrantly expressed on the cell membrane of pancreatic ductal adenocarcinoma (PDAC) cells. 31 Given that inter-and intra-tumor variability can affect the architecture of the tumor vascularization/ microenvironment and, consequently, the passive targeting efficacy, 32 the active targeting strategy exploited herein through anti-Kv11.1-pAb is envisaged to capitalize on the full potential benefit of the nanomedicine developed. Although it is accepted that the enhanced permeation and retention (EPR) effect aids to nanoparticles' passive targeting of tumors, the effectiveness of such targeting strategy can be affected by several factors.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeted polyethylene glycol gold nanoparticles for the treatment of pancreatic cancer: from synthesis to proof-of-concept in vitro studies

Spadavecchia¹,

Movia²,

Moore³

et al. 2016

IJN

167

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International audienceThe main objective of this study was to optimize and characterize a drug delivery carrier for doxorubicin, intended to be intravenously administered, capable of improving the therapeutic index of the chemotherapeutic agent itself, and aimed at the treatment of pancreatic cancer. In light of this goal, we report a robust one-step method for the synthesis of dicarboxylic acid-terminated polyethylene glycol (PEG)-gold nanoparticles (AuNPs) and doxorubicin-loaded PEG-AuNPs, and their further antibody targeting (anti-Kv11.1 polyclonal antibody [pAb]). In in vitro proof-of-concept studies, we evaluated the influence of the nanocarrier and of the active targeting functionality on the anti-tumor efficacy of doxorubicin, with respect to its half-maximal effective concentration (EC50) and drug-triggered changes in the cell cycle. Our results demonstrated that the therapeutic efficacy of doxorubicin was positively influenced not only by the active targeting exploited through anti-Kv11.1-pAb but also by the drug coupling with a nanometer-sized delivery system, which indeed resulted in a 30-fold decrease of doxorubicin EC50, cell cycle blockage, and drug localization in the cell nuclei. The cell internalization pathway was strongly influenced by the active targeting of the Kv11.1 subunit of the human Ether-à-go-go related gene 1 (hERG1) channel aberrantly expressed on the membrane of pancreatic cancer cells. Targeted PEG-AuNPs were translocated into the lysosomes and were associated to an increased lysosomal function in PANC-1 cells. Additionally, doxorubicin release into an aqueous environment was almost negligible after 7 days, suggesting that drug release from PEG-AuNPs was triggered by enzymatic activity. Although preliminary, data gathered from this study have considerable potential in the application of safe-by-design nano-enabled drug-delivery systems (ie, nanomedicines) for the treatment of pancreatic cancer, a disease with a poor prognosis and one of the main current burdens of today’s health care bill of industrialized countries

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“…HERG1 was initially reported to serve important roles in the process of repolarizing cardiac membrane potential (32). HERG1 was identified to be highly expressed in various tumor tissues, and was closely associated with tumor cell proliferation, apoptosis, differentiation, migration and invasion (35)(36)(37).…”

Section: Cell Cycle % Apoptosis % ---------------------------------mentioning

confidence: 99%

Anticancer effect of miR-96 inhibitor in bladder cancer cell lines

et al. 2018

Oncol Lett

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Abstract. The present study aimed to investigate the role of microRNA-96 (miR-96) in the proliferation, invasion and apoptosis of bladder cancer cell lines, and the associated mechanisms. The expression of miR-96 and human ether-à-go-go-related (HERG1) potassium channel in the normal uroepithelium SV-HUC-1 cell line, and bladder cancer T24 and 5637 cell lines were examined using reverse transcription-polymerase chain reaction or/and western blotting. Transfection with miR-96 inhibitor or scrambled control (SC) was used to study the biological activities of miR-96 in bladder cancer cell lines. MTT, flow cytometric and Transwell assays were applied to detect cell viability, apoptosis and invasion, respectively. A dual-luciferase reporter assay was applied to determine the association between miR-96 and HERG1 expression. As demonstrated, miR-96 was highly expressed in the two bladder cancer cell lines, particularly in T24 cells. Following transfection with miR-96 inhibitor, miR-96 expression was significantly reduced in the T24 cell line, compared with SC. The miR-96 inhibitor suppressed cell proliferation and invasion, promoted apoptosis and arrested the cell cycle at the G 1 phase. Consistently, HERG1 was also highly expressed in the two bladder cancer cell lines at the mRNA and protein level, but not in the normal uroepithelium cell line. The miR-96 inhibitor also significantly decreased HERG1 expression compared with SC. The results of the dual-luciferase reporter assay indicated that miR-96 directly targeted wild-type HERG1. In conclusion, miR-96 inhibitor exhibited anticancer effects on bladder cancer cells by inhibiting proliferation and invasion of cells, and promoting their apoptosis. HERG1 was an important target of miR-96. These results provided experimental evidence supporting miR-96 as a therapeutic target for patients with bladder cancer.

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hERG1 Potassium Channels: Novel Biomarkers in Human Solid Cancers

Cited by 41 publications

References 60 publications

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

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

Targeted polyethylene glycol gold nanoparticles for the treatment of pancreatic cancer: from synthesis to proof-of-concept in vitro studies

Anticancer effect of miR-96 inhibitor in bladder cancer cell lines

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