|
1
|
Yu Y, Zhu C, Wang X, Shi Y, Gao Y, Yu Z. hERG activators exhibit antitumor effects in breast cancer through calcineurin and β-catenin-mediated signaling pathways. Front Pharmacol 2025; 16:1545300. [PMID: 39917621 PMCID: PMC11799564 DOI: 10.3389/fphar.2025.1545300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Accepted: 01/06/2025] [Indexed: 02/09/2025] Open
Abstract
Background Breast cancer remains a leading cause of mortality among women worldwide, with existing therapeutic options often accompanied by significant side effects and a persistent risk of disease recurrence. This highlights the need for novel drug candidates with new mechanisms of action by targeting alternative signaling pathways. While hERG channel is notoriously regarded as an off-target due to drug-induced cardiotoxicity, its therapeutic potential as a drug target remains largely unexplored. Methods This study investigated the role of hERG in breast cancer progression and its impact on patient survival. The anti-proliferative, anti-migratory, anti-invasive and pro-apoptotic effects of hERG activators were evaluated using the Cell Counting Kit-8, wound healing assay, transwell assay and cell apoptosis assay, respectively. Western blotting, Ca2+ imaging and immunofluorescence assays were employed to study their antitumor mechanisms of actions. Results We identified two novel hERG activators, SDUY429 and SDUY436, which effectively inhibited the proliferation and migration of MDA-MB-231 and MCF-7 cells. In addition, SDUY436 demonstrated significant anti-invasive and pro-apoptotic effects in MDA-MB-231 cells. Mechanistically, the anti-proliferative activity of hERG activators were mediated through calcineurin activation via enhanced calcium ion influx, which facilitated the nuclear translocation of nuclear factor of activated T cells (NFAT) and upregulated p21Waf/Cip expression. Furthermore, both SDUY429 and SDUY436 remarkably suppressed the migration and invasion of MDA-MB-231 cells by downregulating the protein kinase B (AKT)/glycogen synthase kinase-3 beta (GSK3β)/β-catenin signaling pathway. The observed reduction in phospho-AKT-Ser473 (pAKTS473) expression resulted in the decreased levels of phospho-GSK3β-Ser9 (pGSK3βS9), thereby limiting the nuclear localization of β-catenin, which led to the inhibition of cell migration and invasion. Notably, combining SDUY429 or SDUY436 with the AKT inhibitor MK-2206 produced synergistic anti-proliferative effects. Conclusion These findings suggest that hERG activators hold promise as new potential therapeutic agents for the treatment of breast cancer, paving the way for future investigations into their clinical applications.
Collapse
Affiliation(s)
| | | | | | | | | | - Zhiyi Yu
- Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| |
Collapse
|
|
2
|
Rodriguez R, Müller S, Colombeau L, Solier S, Sindikubwabo F, Cañeque T. Metal Ion Signaling in Biomedicine. Chem Rev 2025; 125:660-744. [PMID: 39746035 PMCID: PMC11758815 DOI: 10.1021/acs.chemrev.4c00577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 11/10/2024] [Accepted: 12/10/2024] [Indexed: 01/04/2025]
Abstract
Complex multicellular organisms are composed of distinct tissues involving specialized cells that can perform specific functions, making such life forms possible. Species are defined by their genomes, and differences between individuals within a given species directly result from variations in their genetic codes. While genetic alterations can give rise to disease-causing acquisitions of distinct cell identities, it is now well-established that biochemical imbalances within a cell can also lead to cellular dysfunction and diseases. Specifically, nongenetic chemical events orchestrate cell metabolism and transcriptional programs that govern functional cell identity. Thus, imbalances in cell signaling, which broadly defines the conversion of extracellular signals into intracellular biochemical changes, can also contribute to the acquisition of diseased cell states. Metal ions exhibit unique chemical properties that can be exploited by the cell. For instance, metal ions maintain the ionic balance within the cell, coordinate amino acid residues or nucleobases altering folding and function of biomolecules, or directly catalyze specific chemical reactions. Thus, metals are essential cell signaling effectors in normal physiology and disease. Deciphering metal ion signaling is a challenging endeavor that can illuminate pathways to be targeted for therapeutic intervention. Here, we review key cellular processes where metal ions play essential roles and describe how targeting metal ion signaling pathways has been instrumental to dissecting the biochemistry of the cell and how this has led to the development of effective therapeutic strategies.
Collapse
Affiliation(s)
- Raphaël Rodriguez
- Institut
Curie, CNRS, INSERM, PSL Research University, 75005 Paris, France
| | - Sebastian Müller
- Institut
Curie, CNRS, INSERM, PSL Research University, 75005 Paris, France
| | - Ludovic Colombeau
- Institut
Curie, CNRS, INSERM, PSL Research University, 75005 Paris, France
| | - Stéphanie Solier
- Institut
Curie, CNRS, INSERM, PSL Research University, 75005 Paris, France
- Université
Paris-Saclay, UVSQ, 78180 Montigny-le-Bretonneux, France
| | | | - Tatiana Cañeque
- Institut
Curie, CNRS, INSERM, PSL Research University, 75005 Paris, France
| |
Collapse
|
|
3
|
Villarruel-Melquiades F, Mendoza-Garrido ME, García-Cuellar CM, Sánchez-Pérez Y, Pérez-Carreón JI, Camacho J. Current and novel approaches in the pharmacological treatment of hepatocellular carcinoma. World J Gastroenterol 2023; 29:2571-2599. [PMID: 37213397 PMCID: PMC10198058 DOI: 10.3748/wjg.v29.i17.2571] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/19/2023] [Accepted: 04/11/2023] [Indexed: 05/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumours worldwide. The mortality-to-incidence ratio is up to 91.6% in many countries, representing the third leading cause of cancer-related deaths. Systemic drugs, including the multikinase inhibitors sorafenib and lenvatinib, are first-line drugs used in HCC treatment. Unfortunately, these therapies are ineffective in most cases due to late diagnosis and the development of tumour resistance. Thus, novel pharmacological alternatives are urgently needed. For instance, immune checkpoint inhibitors have provided new approaches targeting cells of the immune system. Furthermore, monoclonal antibodies against programmed cell death-1 have shown benefits in HCC patients. In addition, drug combinations, including first-line treatment and immunotherapy, as well as drug repurposing, are promising novel therapeutic alternatives. Here, we review the current and novel pharmacological approaches to fight HCC. Preclinical studies, as well as approved and ongoing clinical trials for liver cancer treatment, are discussed. The pharmacological opportunities analysed here should lead to significant improvement in HCC therapy.
Collapse
Affiliation(s)
- Fernanda Villarruel-Melquiades
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico
| | - María Eugenia Mendoza-Garrido
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico
| | - Claudia M García-Cuellar
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Mexico City 14080, Mexico
| | - Yesennia Sánchez-Pérez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Mexico City 14080, Mexico
| | - Julio Isael Pérez-Carreón
- Instituto Nacional de Medicina Genómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico
| | - Javier Camacho
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico
| |
Collapse
|
|
4
|
Chen CY, Wu PY, Van Scoyk M, Simko SA, Chou CF, Winn RA. KCNF1 promotes lung cancer by modulating ITGB4 expression. Cancer Gene Ther 2023; 30:414-423. [PMID: 36385523 PMCID: PMC10014577 DOI: 10.1038/s41417-022-00560-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 10/20/2022] [Accepted: 11/01/2022] [Indexed: 11/17/2022]
Abstract
Lung cancer continues to be the leading cause of cancer death in the United States. Despite recent advances, the five-year survival rate for lung cancer compared to other cancers still remains fairly low. The discovery of molecular targets for lung cancer is key to the development of new approaches and therapies. Electrically silent voltage-gated potassium channel (KvS) subfamilies, which are unable to form functional homotetramers, are implicated in cell-cycle progression, cell proliferation and tumorigenesis. Here, we analyzed the expression of KvS subfamilies in human lung tumors and identified that potassium voltage-gated channel subfamily F member 1 (KCNF1) was up-regulated in non-small cell lung cancer (NSCLC). Silencing of KCNF1 in NSCLC cell lines reduced cell proliferation and tumor progression in mouse xenografts, re-established the integrity of the basement membrane, and enhanced cisplatin sensitivity. KCNF1 was predominately localized in the nucleoplasm and likely mediated its functions in an ion-independent manner. We identified integrin β4 subunit (ITGB4) as a downstream target for KCNF1. Our findings suggest that KCNF1 promotes lung cancer by enhancing ITGB4 signaling and implicate KCNF1 as a novel therapeutic target for lung cancer.
Collapse
Affiliation(s)
- Ching-Yi Chen
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Pei-Ying Wu
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Michelle Van Scoyk
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Stephanie A Simko
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Chu-Fang Chou
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Robert A Winn
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
| |
Collapse
|
|
5
|
Soohoo SM, Tiwari PB, Suzuki YJ, Brelidze TI. Investigation of PAS and CNBH domain interactions in hERG channels and effects of long-QT syndrome-causing mutations with surface plasmon resonance. J Biol Chem 2021; 298:101433. [PMID: 34801551 PMCID: PMC8693265 DOI: 10.1016/j.jbc.2021.101433] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 11/29/2022] Open
Abstract
Human ether-á-go-go-related gene (hERG) channels are key regulators of cardiac repolarization, neuronal excitability, and tumorigenesis. hERG channels contain N-terminal Per-Arnt-Sim (PAS) and C-terminal cyclic nucleotide-binding homology (CNBH) domains with many long-QT syndrome (LQTS)-causing mutations located at the interface between these domains. Despite the importance of PAS/CNBH domain interactions, little is known about their affinity. Here, we used the surface plasmon resonance (SPR) technique to investigate interactions between isolated PAS and CNBH domains and the effects of LQTS-causing mutations R20G, N33T, and E58D, located at the PAS/CNBH domain interface, on these interactions. We determined that the affinity of the PAS/CNBH domain interactions was ∼1.4 μM. R20G and E58D mutations had little effect on the domain interaction affinity, while N33T abolished the domain interactions. Interestingly, mutations in the intrinsic ligand, a conserved stretch of amino acids occupying the beta-roll cavity in the CNBH domain, had little effect on the affinity of PAS/CNBH domain interactions. Additionally, we determined that the isolated PAS domains formed oligomers with an interaction affinity of ∼1.6 μM. Coexpression of the isolated PAS domains with the full-length hERG channels or addition of the purified PAS protein inhibited hERG currents. These PAS/PAS interactions can have important implications for hERG function in normal and pathological conditions associated with increased surface density of channels or interaction with other PAS-domain-containing proteins. Taken together, our study provides the first account of the binding affinities for wild-type and mutant hERG PAS and CNBH domains and highlights the potential functional significance of PAS/PAS domain interactions.
Collapse
Affiliation(s)
- Stephanie M Soohoo
- Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Purushottam B Tiwari
- Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Yuichiro J Suzuki
- Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Tinatin I Brelidze
- Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, District of Columbia, USA.
| |
Collapse
|
|
6
|
Chen J, Zhang M, Ma Z, Yuan D, Zhu J, Tuo B, Li T, Liu X. Alteration and dysfunction of ion channels/transporters in a hypoxic microenvironment results in the development and progression of gastric cancer. Cell Oncol (Dordr) 2021; 44:739-749. [PMID: 33856653 PMCID: PMC8338819 DOI: 10.1007/s13402-021-00604-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/19/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common malignant cancers in the world and has only few treatment options and, concomitantly, a poor prognosis. It is generally accepted now that the tumor microenvironment, particularly that under hypoxia, plays an important role in cancer development. Hypoxia can regulate the energy metabolism and malignancy of tumor cells by inducing or altering various important factors, such as oxidative stress, reactive oxygen species (ROS), hypoxia-inducible factors (HIFs), autophagy and acidosis. In addition, altered expression and/or dysfunction of ion channels/transporters (ICTs) have been encountered in a variety of human tumors, including GC, and to play an important role in the processes of tumor cell proliferation, migration, invasion and apoptosis. Increasing evidence indicates that ICTs are at least partly involved in interactions between cancer cells and their hypoxic microenvironment. Here, we provide an overview of the different ICTs that regulate or are regulated by hypoxia in GC. CONCLUSIONS AND PERSPECTIVES Hypoxia is one of the major obstacles to cancer therapy. Regulating cellular responses and factors under hypoxia can inhibit GC. Similarly, altering the expression or activity of ICTs, such as the application of ion channel inhibitors, can slow down the growth and/or migration of GC cells. Since targeting the hypoxic microenvironment and/or ICTs may be a promising strategy for the treatment of GC, more attention should be paid to the interplay between ICTs and the development and progression of GC in such a microenvironment.
Collapse
Affiliation(s)
- Junling Chen
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou Province, China
- Digestive Disease Institute of Guizhou Province, Zunyi, Guizhou Province, China
| | - Minglin Zhang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou Province, China
- Digestive Disease Institute of Guizhou Province, Zunyi, Guizhou Province, China
| | - Zhiyuan Ma
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou Province, China
- Digestive Disease Institute of Guizhou Province, Zunyi, Guizhou Province, China
- Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou Province, China
| | - Dumin Yuan
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou Province, China
- Digestive Disease Institute of Guizhou Province, Zunyi, Guizhou Province, China
| | - Jiaxing Zhu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou Province, China
- Digestive Disease Institute of Guizhou Province, Zunyi, Guizhou Province, China
| | - Biguang Tuo
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou Province, China
- Digestive Disease Institute of Guizhou Province, Zunyi, Guizhou Province, China
| | - Taolang Li
- Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou Province, China.
| | - Xuemei Liu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou Province, China.
- Digestive Disease Institute of Guizhou Province, Zunyi, Guizhou Province, China.
| |
Collapse
|
|
7
|
Shiozaki A, Marunaka Y, Otsuji E. Roles of Ion and Water Channels in the Cell Death and Survival of Upper Gastrointestinal Tract Cancers. Front Cell Dev Biol 2021; 9:616933. [PMID: 33777930 PMCID: PMC7991738 DOI: 10.3389/fcell.2021.616933] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 02/22/2021] [Indexed: 02/06/2023] Open
Abstract
Ion and water channels were recently shown to be involved in cancer cell functions, and various transporter types have been detected in upper gastrointestinal tract (UGI) cancers. Current information on the expression and roles of these channels and transporters in the death and survival of UGI cancer cells was reviewed herein, and the potential of their regulation for cancer management was investigated. Esophageal cancer (EC) and gastric cancer (GC) cells and tissues express many different types of ion channels, including voltage-gated K+, Cl-, and Ca2+, and transient receptor potential (TRP) channels, which regulate the progression of cancer. Aquaporin (AQP) 1, 3, and 5 are water channels that contribute to the progression of esophageal squamous cell carcinoma (ESCC) and GC. Intracellular pH regulators, including the anion exchanger (AE), sodium hydrogen exchanger (NHE), and vacuolar H+-ATPases (V-ATPase), also play roles in the functions of UGI cancer cells. We have previously conducted gene expression profiling and revealed that the regulatory mechanisms underlying apoptosis in ESCC cells involved various types of Cl- channels, Ca2+ channels, water channels, and pH regulators (Shimizu et al., 2014; Ariyoshi et al., 2017; Shiozaki et al., 2017, 2018a; Kobayashi et al., 2018; Yamazato et al., 2018; Konishi et al., 2019; Kudou et al., 2019; Katsurahara et al., 2020, 2021; Matsumoto et al., 2021; Mitsuda et al., 2021). We have also previously demonstrated the clinicopathological and prognostic significance of their expression in ESCC patients, and shown that their pharmacological blockage and gene silencing had an impact on carcinogenesis, indicating their potential as targets for the treatment of UGI cancers. A more detailed understanding of the molecular regulatory mechanisms underlying cell death and survival of UGI cancers may result in the application of cellular physiological methods as novel therapeutic approaches.
Collapse
Affiliation(s)
- Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshinori Marunaka
- Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.,Research Institute for Clinical Physiology, Kyoto Industrial Health Association, Kyoto, Japan.,Research Center for Drug Discovery and Pharmaceutical Development Science, Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| |
Collapse
|
|
8
|
Bachmann M, Li W, Edwards MJ, Ahmad SA, Patel S, Szabo I, Gulbins E. Voltage-Gated Potassium Channels as Regulators of Cell Death. Front Cell Dev Biol 2020; 8:611853. [PMID: 33381507 PMCID: PMC7767978 DOI: 10.3389/fcell.2020.611853] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 11/23/2020] [Indexed: 12/11/2022] Open
Abstract
Ion channels allow the flux of specific ions across biological membranes, thereby determining ion homeostasis within the cells. Voltage-gated potassium-selective ion channels crucially contribute to the setting of the plasma membrane potential, to volume regulation and to the physiologically relevant modulation of intracellular potassium concentration. In turn, these factors affect cell cycle progression, proliferation and apoptosis. The present review summarizes our current knowledge about the involvement of various voltage-gated channels of the Kv family in the above processes and discusses the possibility of their pharmacological targeting in the context of cancer with special emphasis on Kv1.1, Kv1.3, Kv1.5, Kv2.1, Kv10.1, and Kv11.1.
Collapse
Affiliation(s)
- Magdalena Bachmann
- Department of Biology, University of Padova, Padua, Italy.,Department of Surgery, Medical School, University of Cincinnati, Cincinnati, OH, United States
| | - Weiwei Li
- Department of Surgery, Medical School, University of Cincinnati, Cincinnati, OH, United States
| | - Michael J Edwards
- Department of Surgery, Medical School, University of Cincinnati, Cincinnati, OH, United States
| | - Syed A Ahmad
- Department of Surgery, Medical School, University of Cincinnati, Cincinnati, OH, United States
| | - Sameer Patel
- Department of Surgery, Medical School, University of Cincinnati, Cincinnati, OH, United States
| | - Ildiko Szabo
- Department of Biology, University of Padova, Padua, Italy.,Consiglio Nazionale delle Ricerche Institute of Neuroscience, Padua, Italy
| | - Erich Gulbins
- Department of Surgery, Medical School, University of Cincinnati, Cincinnati, OH, United States.,Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany
| |
Collapse
|
|
9
|
Capatina AL, Lagos D, Brackenbury WJ. Targeting Ion Channels for Cancer Treatment: Current Progress and Future Challenges. Rev Physiol Biochem Pharmacol 2020; 183:1-43. [PMID: 32865696 DOI: 10.1007/112_2020_46] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ion channels are key regulators of cancer cell pathophysiology. They contribute to a variety of processes such as maintenance of cellular osmolarity and membrane potential, motility (via interactions with the cytoskeleton), invasion, signal transduction, transcriptional activity and cell cycle progression, leading to tumour progression and metastasis. Ion channels thus represent promising targets for cancer therapy. Ion channels are attractive targets because many of them are expressed at the plasma membrane and a broad range of existing inhibitors are already in clinical use for other indications. However, many of the ion channels identified in cancer cells are also active in healthy normal cells, so there is a risk that certain blockers may have off-target effects on normal physiological function. This review describes recent research advances into ion channel inhibitors as anticancer therapeutics. A growing body of evidence suggests that a range of existing and novel Na+, K+, Ca2+ and Cl- channel inhibitors may be effective for suppressing cancer cell proliferation, migration and invasion, as well as enhancing apoptosis, leading to suppression of tumour growth and metastasis, either alone or in combination with standard-of-care therapies. The majority of evidence to date is based on preclinical in vitro and in vivo studies, although there are several examples of ion channel-targeting strategies now reaching early phase clinical trials. Given the strong links between ion channel function and regulation of tumour growth, metastasis and chemotherapy resistance, it is likely that further work in this area will facilitate the development of new therapeutic approaches which will reach the clinic in the future.
Collapse
Affiliation(s)
| | - Dimitris Lagos
- Hull York Medical School, York, UK
- York Biomedical Research Institute, University of York, York, UK
| | - William J Brackenbury
- Department of Biology, University of York, York, UK.
- York Biomedical Research Institute, University of York, York, UK.
| |
Collapse
|
|
10
|
Assiri AA, Mourad N, Shao M, Kiel P, Liu W, Skaar TC, Overholser BR. MicroRNA 362-3p Reduces hERG-related Current and Inhibits Breast Cancer Cells Proliferation. Cancer Genomics Proteomics 2020; 16:433-442. [PMID: 31659098 DOI: 10.21873/cgp.20147] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 08/27/2019] [Accepted: 08/29/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND/AIM hERG potassium channels enhance tumor invasiveness and breast cancer proliferation. MicroRNA (miRNA) dysregulation during cancer controls gene regulation. The objective of this study was to identify miRNAs that regulate hERG expression in breast cancer. MATERIALS AND METHODS Putative miRNAs targeting hERG were identified by bioinformatic approaches and screened using a 3'UTR luciferase assay. Functional assessments of endogenous hERG regulation were made using whole-cell electrophysiology, proliferation assays, and cell-cycle analyses following miRNA, hERG siRNA, or control transfection. RESULTS miR-362-3p targeted hERG 3'UTR and was associated with higher survival rates in patients with breast cancer (HR=0.39, 95%CI=0.18-0.82). Enhanced miR-362-3p expression reduced hERG expression, peak current, and cell proliferation in cultured breast cancer cells (p<0.05). CONCLUSION miR-362-3p mediates the transcriptional regulation of hERG and is associated with survival in breast cancer. The potential for miR-362-3p to serve as a biomarker and inform therapeutic strategies warrants further investigation.
Collapse
Affiliation(s)
- Abdullah A Assiri
- Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette, IN, U.S.A.,Department of Clinical Pharmacy, King Khalid University, Abha, Kingdom of Saudi Arabia
| | - Noha Mourad
- Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette, IN, U.S.A.,College of Pharmacy, Manchester University, Fort Wayne, IN, U.S.A
| | - Minghai Shao
- Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette, IN, U.S.A
| | - Patrick Kiel
- Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, U.S.A
| | - Wanqing Liu
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, U.S.A
| | - Todd C Skaar
- Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, U.S.A
| | - Brian R Overholser
- Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette, IN, U.S.A. .,Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, U.S.A
| |
Collapse
|
|
11
|
Lastraioli E, Romoli MR, Iorio J, Lottini T, Chiudinelli M, Bencivenga M, Vindigni C, Tomezzoli A, De Manzoni G, Compagnoni B, Manzi I, Messerini L, Saragoni L, Arcangeli A. The hERG1 Potassium Channel Behaves As Prognostic Factor In Gastric Dysplasia Endoscopic Samples. Onco Targets Ther 2019; 12:9377-9384. [PMID: 31807018 PMCID: PMC6844225 DOI: 10.2147/ott.s226257] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 10/16/2019] [Indexed: 12/25/2022] Open
Abstract
Purpose Gastric cancer (GC) is still a relevant health issue worldwide. The identification of prognostic factors for progression of gastric dysplasia (GD), the main pre-cancerous lesion of the intestinal-type GC, is hence mandatory. Patients and methods A cohort of 83 GD endoscopic samples belonging to Italian subjects was collected. hERG1 expression was evaluated by immunohistochemistry and scored 0–3, depending on the percentage of stained cells. Expression data were analysed in conjunction with clinico-pathological and survival data. Results hERG1 turned out to be expressed in 67.47% (56 out of 83) of the GD samples. hERG1 expression was higher in high-grade GD compared to low-grade GD (29 out of 39, 74.36% vs 27 out of 44, 61.36%), although the statistical significance was not reached (P=0.246). No association emerged between hERG1 expression and clinical features of the patients (age, gender, localization, H. pylori infection, gastritis and intestinal metaplasia). In a subset of cases for which sequential samples of gastric lesions (from GD to Early Gastric Cancer and Advanced Gastric Cancer) were available, hERG1 expression was maintained in all the steps of gastric carcinogenesis from GD onwards. A general trend to increased expression in advanced lesions was observed. hERG1 score had a statistically significant impact on both Progression-Free Survival (P=0.018) and Overall Survival (P=0.031). In particular, patients displaying a high hERG1 score have a shorter survival. Conclusion hERG1 is aberrantly expressed in human GD samples and has an impact on both PFS and OS, hence representing a novel prognostic marker for progression of GD towards GC of the intestinal histotype. Once properly validated, hERG1 detection could be included in the clinical practice, during endoscopic surveillance protocols, for the management of GD at higher risk of progression, as already proposed for Barrett’s oesophagus.
Collapse
Affiliation(s)
- Elena Lastraioli
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University Of Florence, Florence 50134, Italy
| | - Maria Raffaella Romoli
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University Of Florence, Florence 50134, Italy
| | - Jessica Iorio
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University Of Florence, Florence 50134, Italy
| | - Tiziano Lottini
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University Of Florence, Florence 50134, Italy
| | - Mariella Chiudinelli
- Pathology Division, Esine Hospital, ASST della Valcamonica, Esine, BS 25040, Italy
| | | | - Carla Vindigni
- Pathology Division, Azienda Ospedaliero-Universitaria Senese, Siena 53100, Italy
| | - Anna Tomezzoli
- Pathology Division, Borgo Trento Hospital, Verona 37134, Italy
| | | | - Bruno Compagnoni
- Surgery Division, Esine Hospital, ASST della Valcamonica, Esine, BS 25040, Italy
| | - Ilaria Manzi
- Gastroenterology and Endoscopy Unit, Morgagni-Pierantoni Hospital, Forlì 47121, Italy
| | - Luca Messerini
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University Of Florence, Florence 50134, Italy
| | - Luca Saragoni
- Pathology Division, Morgagni-Pierantoni Hospital, Forlì 47121, Italy
| | - Annarosa Arcangeli
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University Of Florence, Florence 50134, Italy
| | | |
Collapse
|
|
12
|
Vaddi DR, Piao L, Khan SA, Wang N, Prabhakar NR, Nanduri J. Hypoxia induced hERG trafficking defect linked to cell cycle arrest in SH-SY5Y cells. PLoS One 2019; 14:e0215905. [PMID: 31017964 PMCID: PMC6481834 DOI: 10.1371/journal.pone.0215905] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 04/10/2019] [Indexed: 11/18/2022] Open
Abstract
The alpha subunit of the voltage gated human ether-a-go-go-related (hERG) potassium channel regulates cell excitability in a broad range of cell lines. HERG channels are also expressed in a variety of cancer cells and control cell proliferation and apoptosis. Hypoxia, a common feature of tumors, alters gating properties of hERG currents in SH-SY5Y neuroblastoma cells. In the present study, we examined the molecular mechanisms and physiological significance underlying hypoxia-altered hERG currents in SH-SY5Y neuroblastoma cells. Hypoxia reduced the surface expression of 150kDa form and increased 125kDa form of hERG protein expression in the endoplasmic reticulum (ER). The changes in protein expression were associated with ~50% decrease in hERG potassium conductance. ER retention of hERG 125kDa form by CH was due to defective trafficking and was rescued by exposing cells to hypoxia at low temperatures or treatment with E-4031, a hERG channel blocker. Prolonged association of hERG with molecular chaperone Hsp90 resulting in complex oligomeric insoluble aggregates contributed to ER accumulation and trafficking defect. Hypoxia increased reactive oxygen species (ROS) levels and manganese (111) tetrakis (1methyl-4-pyridyl) porphyrin pentachloride, a membrane-permeable antioxidant prevented hypoxia-induced degradation of 150kDa and accumulation of 125kDa forms. Impaired trafficking of hERG by hypoxia was associated with reduced cell proliferation and this effect was prevented by antioxidant treatment. These results demonstrate that hypoxia through increased oxidative stress impairs hERG trafficking, leading to decreased K+ currents resulting in cell cycle arrest in SH-SY5Y cells.
Collapse
Affiliation(s)
- Damodara Reddy Vaddi
- Institute for Integrative Physiology, Center for Systems Biology of O2 Sensing, Biological Sciences Division, The University of Chicago, Chicago, Illinois, United States of America
| | - Lin Piao
- Institute for Integrative Physiology, Center for Systems Biology of O2 Sensing, Biological Sciences Division, The University of Chicago, Chicago, Illinois, United States of America
| | - Shakil A. Khan
- Institute for Integrative Physiology, Center for Systems Biology of O2 Sensing, Biological Sciences Division, The University of Chicago, Chicago, Illinois, United States of America
| | - Ning Wang
- Institute for Integrative Physiology, Center for Systems Biology of O2 Sensing, Biological Sciences Division, The University of Chicago, Chicago, Illinois, United States of America
| | - Nanduri R. Prabhakar
- Institute for Integrative Physiology, Center for Systems Biology of O2 Sensing, Biological Sciences Division, The University of Chicago, Chicago, Illinois, United States of America
| | - Jayasri Nanduri
- Institute for Integrative Physiology, Center for Systems Biology of O2 Sensing, Biological Sciences Division, The University of Chicago, Chicago, Illinois, United States of America
| |
Collapse
|
|
13
|
Shah RR, Stonier PD. Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead. J Clin Pharm Ther 2018; 44:6-22. [PMID: 30218625 DOI: 10.1111/jcpt.12759] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 08/08/2018] [Accepted: 08/19/2018] [Indexed: 12/11/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE In order to expedite the availability of drugs to treat cancers in a cost-effective manner, repurposing of old drugs for oncological indications is gathering momentum. Revolutionary advances in pharmacology and genomics have demonstrated many old drugs to have activity at novel antioncogenic pharmacological targets. We decided to investigate whether prospective studies support the promises of nonclinical and retrospective clinical studies on repurposing three old drugs, namely metformin, valproate and astemizole. METHODS We conducted an extensive literature search through PubMed to gather representative nonclinical and retrospective clinical studies that investigated the potential repurposing of these three drugs for oncological indications. We then searched for prospective studies aimed at confirming the promises of retrospective data. RESULTS AND DISCUSSION While evidence from nonclinical and retrospective clinical studies with these drugs appears highly promising, large scale prospective studies are either lacking or have failed to substantiate this promise. We provide a brief discussion of some of the challenges in repurposing. Principal challenges and obstacles relate to heterogeneity of cancers studied without considering their molecular signatures, trials with small sample size and short duration, failure consider issues of ethnicity of study population and effective antioncogenic doses of the drug studied. WHAT IS NEW AND CONCLUSION Well-designed prospective studies demonstrating efficacy are required for repurposing old drugs for oncology indications, just as they are for new chemical entities for any indication. Early and ongoing interactions with regulatory authorities are invaluable. We outline a tentative framework for a structured approach to repurposing old drugs for novel indications in oncology.
Collapse
Affiliation(s)
- Rashmi R Shah
- Pharmaceutical Consultant, Gerrards Cross, Buckinghamshire, UK
| | - Peter D Stonier
- Department of Pharmaceutical Medicine, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King's College, London, UK
| |
Collapse
|
|
14
|
Han J, Lee SH, Giebisch G, Wang T. Potassium Channelopathies and Gastrointestinal Ulceration. Gut Liver 2017; 10:881-889. [PMID: 27784845 PMCID: PMC5087926 DOI: 10.5009/gnl15414] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 10/14/2015] [Accepted: 10/20/2015] [Indexed: 12/13/2022] Open
Abstract
Potassium channels and transporters maintain potassium homeostasis and play significant roles in several different biological actions via potassium ion regulation. In previous decades, the key revelations that potassium channels and transporters are involved in the production of gastric acid and the regulation of secretion in the stomach have been recognized. Drugs used to treat peptic ulceration are often potassium transporter inhibitors. It has also been reported that potassium channels are involved in ulcerative colitis. Direct toxicity to the intestines from nonsteroidal anti-inflammatory drugs has been associated with altered potassium channel activities. Several reports have indicated that the long-term use of the antianginal drug Nicorandil, an adenosine triphosphate-sensitive potassium channel opener, increases the chances of ulceration and perforation from the oral to anal regions throughout the gastrointestinal (GI) tract. Several of these drug features provide further insights into the role of potassium channels in the occurrence of ulceration in the GI tract. The purpose of this review is to investigate whether potassium channelopathies are involved in the mechanisms responsible for ulceration that occurs throughout the GI tract.
Collapse
Affiliation(s)
- Jaeyong Han
- Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA
| | - Seung Hun Lee
- Department of Internal Medicine, Section of Nephrology, Yale University, New Haven, CT, USA
| | - Gerhard Giebisch
- Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA
| | - Tong Wang
- Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA
| |
Collapse
|
|
15
|
Gentile S. hERG1 potassium channel in cancer cells: a tool to reprogram immortality. EUROPEAN BIOPHYSICS JOURNAL: EBJ 2016; 45:649-655. [PMID: 27649700 DOI: 10.1007/s00249-016-1169-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/31/2015] [Revised: 07/21/2016] [Accepted: 08/30/2016] [Indexed: 12/12/2022]
Abstract
It has been well established that changes in ion fluxes across cellular membranes as a function of time is fundamental in maintaining cellular homeostasis of every living cell. Consequently, dysregulation of ion channels activity is a critical event in pathological conditions of several tissues, including cancer. Nevertheless, the role of ion channels in cancer biology is still not well understood and very little is known about the possible therapeutic opportunities offered by the use of the vast collection of drugs that target ion channels. In this review, we focus on the recent advances in understanding the role of the voltage-gated hERG1 potassium channel in cancer and on the effects of pharmacologic manipulation of the hERG1 in cancer cells aiming to provide insights into the biochemical signaling and cellular processes that are altered by using these drugs.
Collapse
|
|
16
|
Wang B, Liu Z, Ma Z, Li M, Du L. Astemizole Derivatives as Fluorescent Probes for hERG Potassium Channel Imaging. ACS Med Chem Lett 2016; 7:245-9. [PMID: 26985309 DOI: 10.1021/acsmedchemlett.5b00360] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 01/20/2016] [Indexed: 01/28/2023] Open
Abstract
The detection and imaging of hERG potassium channels in living cells can provide useful information for hERG-correlation studies. Herein, three small-molecule fluorescent probes, based on the potent hERG channel inhibitor astemizole, for the imaging of hERG channels in hERG-transfected HEK293 cells (hERG-HEK293) and human colorectal cancer cells (HT-29), are described. These probes are expected to be applied in the physiological and pathological studies of hERG channels.
Collapse
Affiliation(s)
- Beilei Wang
- Department of Medicinal Chemistry,
Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Zhenzhen Liu
- Department of Medicinal Chemistry,
Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Zhao Ma
- Department of Medicinal Chemistry,
Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Minyong Li
- Department of Medicinal Chemistry,
Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Lupei Du
- Department of Medicinal Chemistry,
Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| |
Collapse
|
|
17
|
Arcangeli A, Becchetti A. Novel perspectives in cancer therapy: Targeting ion channels. Drug Resist Updat 2015; 21-22:11-9. [DOI: 10.1016/j.drup.2015.06.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2015] [Revised: 06/24/2015] [Accepted: 06/27/2015] [Indexed: 01/04/2023]
|
|
18
|
Bose T, Cieślar-Pobuda A, Wiechec E. Role of ion channels in regulating Ca²⁺ homeostasis during the interplay between immune and cancer cells. Cell Death Dis 2015; 6:e1648. [PMID: 25695601 PMCID: PMC4669790 DOI: 10.1038/cddis.2015.23] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Revised: 12/23/2014] [Accepted: 01/06/2015] [Indexed: 01/08/2023]
Abstract
Ion channels are abundantly expressed in both excitable and non-excitable cells, thereby regulating the Ca2+ influx and downstream signaling pathways of physiological processes. The immune system is specialized in the process of cancer cell recognition and elimination, and is regulated by different ion channels. In comparison with the immune cells, ion channels behave differently in cancer cells by making the tumor cells more hyperpolarized and influence cancer cell proliferation and metastasis. Therefore, ion channels comprise an important therapeutic target in anti-cancer treatment. In this review, we discuss the implication of ion channels in regulation of Ca2+ homeostasis during the crosstalk between immune and cancer cell as well as their role in cancer progression.
Collapse
Affiliation(s)
- T Bose
- Leibniz-Institute of Neurobiology, Brenneckestrasse 6, D-39 Magdeburg, Germany
| | - A Cieślar-Pobuda
- 1] Department of Clinical and Experimental Medicine, Division of Cell Biology & Integrative Regenerative Medicine Center (IGEN), Linköping University, 581 85 Linköping, Sweden [2] Biosystems Group, Institute of Automatic Control, Silesian University of Technology, Akademicka 16, 44-100 Gliwice, Poland
| | - E Wiechec
- Department of Clinical and Experimental Medicine, Division of Cell Biology & Integrative Regenerative Medicine Center (IGEN), Linköping University, 581 85 Linköping, Sweden
| |
Collapse
|
|
19
|
Ion channel expression as promising cancer biomarker. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2014; 1848:2685-702. [PMID: 25542783 DOI: 10.1016/j.bbamem.2014.12.016] [Citation(s) in RCA: 140] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Revised: 12/10/2014] [Accepted: 12/16/2014] [Indexed: 12/11/2022]
Abstract
Cancer is a disease with marked heterogeneity in both response to therapy and survival. Clinical and histopathological characteristics have long determined prognosis and therapy. The introduction of molecular diagnostics has heralded an explosion in new prognostic factors. Overall, histopathology, immunohistochemistry and molecular biology techniques have described important new prognostic subgroups in the different cancer categories. Ion channels and transporters (ICT) are a new class of membrane proteins which are aberrantly expressed in several types of human cancers. Besides regulating different aspect of cancer cell behavior, ICT can now represent novel cancer biomarkers. A summary of the data obtained so far and relative to breast, prostate, lung, colorectal, esophagus, pancreatic and gastric cancers are reported. Special emphasis is given to those studies aimed at relating specific ICT or a peculiar ICT profile with current diagnostic methods. Overall, we are close to exploit ICTs for diagnostic, prognostic or predictive purposes in cancer. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
Collapse
|
|
20
|
Involvement of potassium channels in the progression of cancer to a more malignant phenotype. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2014; 1848:2477-92. [PMID: 25517985 DOI: 10.1016/j.bbamem.2014.12.008] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Revised: 12/01/2014] [Accepted: 12/08/2014] [Indexed: 12/22/2022]
Abstract
Potassium channels are a diverse group of pore-forming transmembrane proteins that selectively facilitate potassium flow through an electrochemical gradient. They participate in the control of the membrane potential and cell excitability in addition to different cell functions such as cell volume regulation, proliferation, cell migration, angiogenesis as well as apoptosis. Because these physiological processes are essential for the correct cell function, K+ channels have been associated with a growing number of diseases including cancer. In fact, different K+ channel families such as the voltage-gated K+ channels, the ether à-go-go K+ channels, the two pore domain K+ channels and the Ca2+-activated K+ channels have been associated to tumor biology. Potassium channels have a role in neoplastic cell-cycle progression and their expression has been found abnormal in many types of tumors and cancer cells. In addition, the expression and activity of specific K+ channels have shown a significant correlation with the tumor malignancy grade. The aim of this overview is to summarize published data on K+ channels that exhibit oncogenic properties and have been linked to a more malignant cancer phenotype. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
Collapse
|
|
21
|
Mitcheson J, Arcangeli A. The Therapeutic Potential of hERG1 K+ Channels for Treating Cancer and Cardiac Arrhythmias. ION CHANNEL DRUG DISCOVERY 2014. [DOI: 10.1039/9781849735087-00258] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
hERG potassium channels present pharmacologists and medicinal chemists with a dilemma. On the one hand hERG is a major reason for drugs being withdrawn from the market because of drug induced long QT syndrome and the associated risk of inducing sudden cardiac death, and yet hERG blockers are still widely used in the clinic to treat cardiac arrhythmias. Moreover, in the last decade overwhelming evidence has been provided that hERG channels are aberrantly expressed in cancer cells and that they contribute to tumour cell proliferation, resistance to apoptosis, and neoangiogenesis. Here we provide an overview of the properties of hERG channels and their role in excitable cells of the heart and nervous system as well as in cancer. We consider the therapeutic potential of hERG, not only with regard to the negative impact due to drug induced long QT syndrome, but also its future potential as a treatment in the fight against cancer.
Collapse
Affiliation(s)
- John Mitcheson
- University of Leicester, Department of Cell Physiology and Pharmacology, Medical Sciences Building University Road Leicester LE1 9HN UK
| | - Annarosa Arcangeli
- Department of Experimental Pathology and Oncology, University of Florence Viale GB Morgagni, 50 50134 Firenze Italy
| |
Collapse
|
|
22
|
The K-Cl cotransporter KCC3 as an independent prognostic factor in human esophageal squamous cell carcinoma. BIOMED RESEARCH INTERNATIONAL 2014; 2014:936401. [PMID: 25110711 PMCID: PMC4119626 DOI: 10.1155/2014/936401] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Accepted: 06/16/2014] [Indexed: 01/02/2023]
Abstract
The objectives of the present study were to investigate the role of K–Cl cotransporter 3 (KCC3) in the regulation of cellular invasion and the clinicopathological significance of its expression in esophageal squamous cell carcinoma (ESCC). Immunohistochemical analysis performed on 70 primary tumor samples obtained from ESCC patients showed that KCC3 was primarily found in the cytoplasm of carcinoma cells. Although the expression of KCC3 in the main tumor (MT) was related to several clinicopathological features, such as the pT and pN categories, it had no prognostic impact. KCC3 expression scores were compared between the MT and cancer nest (CN), and the survival rate of patients with a CN > MT score was lower than that of patients with a CN ≤ MT score. In addition, the survival rate of patients in whom KCC3 was expressed in the invasive front of tumor was lower than that of the patients without it. Furthermore, multivariate analysis demonstrated that the expression of KCC3 in the invasive front was one of the most important independent prognostic factors. The depletion of KCC3 using siRNAs inhibited cell migration and invasion in human ESCC cell lines. These results suggest that the expression of KCC3 in ESCC may affect cellular invasion and be related to a worse prognosis in patients with ESCC.
Collapse
|
|
23
|
Shiozaki A, Nako Y, Ichikawa D, Konishi H, Komatsu S, Kubota T, Fujiwara H, Okamoto K, Kishimoto M, Marunaka Y, Otsuji E. Role of the Na +/K +/2Cl - cotransporter NKCC1 in cell cycle progression in human esophageal squamous cell carcinoma. World J Gastroenterol 2014; 20:6844-6859. [PMID: 24944475 PMCID: PMC4051924 DOI: 10.3748/wjg.v20.i22.6844] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/17/2014] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of Na+/K+/2Cl- cotransporter 1 (NKCC1) in the regulation of genes involved in cell cycle progression and the clinicopathological significance of its expression in esophageal squamous cell carcinoma (ESCC).
METHODS: An immunohistochemical analysis was performed on 68 primary tumor samples obtained from ESCC patients that underwent esophagectomy. NKCC1 expression in human ESCC cell lines was analyzed by Western blotting. Knockdown experiments were conducted using NKCC1 small interfering RNA, and the effects on cell cycle progression were analyzed. The gene expression profiles of cells were analyzed by microarray analysis.
RESULTS: Immunohistochemical staining showed that NKCC1 was primarily found in the cytoplasm of carcinoma cells and that its expression was related to the histological degree of differentiation of SCC. NKCC1 was highly expressed in KYSE170 cells. Depletion of NKCC1 in these cells inhibited cell proliferation via G2/M phase arrest. Microarray analysis identified 2527 genes with altered expression levels in NKCC1depleted KYSE170. Pathway analysis showed that the top-ranked canonical pathway was the G2/M DNA damage checkpoint regulation pathway, which involves MAD2L1, DTL, BLM, CDC20, BRCA1, and E2F5.
CONCLUSION: These results suggest that the expression of NKCC1 in ESCC may affect the G2/M checkpoint and may be related to the degree of histological differentiation of SCCs. We have provided a deeper understanding of the role of NKCC1 as a mediator and/or a biomarker in ESCC.
Collapse
MESH Headings
- Aged
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Blotting, Western
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/pathology
- Cell Cycle Proteins/genetics
- Cell Cycle Proteins/metabolism
- Cell Differentiation
- Cell Line, Tumor
- Cell Proliferation
- Esophageal Neoplasms/genetics
- Esophageal Neoplasms/metabolism
- Esophageal Neoplasms/pathology
- Esophageal Squamous Cell Carcinoma
- Female
- G2 Phase Cell Cycle Checkpoints/drug effects
- Gene Expression Profiling/methods
- Gene Expression Regulation, Neoplastic
- Gene Regulatory Networks
- Humans
- Immunohistochemistry
- Male
- Middle Aged
- Oligonucleotide Array Sequence Analysis
- RNA Interference
- Signal Transduction
- Sodium Potassium Chloride Symporter Inhibitors/pharmacology
- Solute Carrier Family 12, Member 2/drug effects
- Solute Carrier Family 12, Member 2/genetics
- Solute Carrier Family 12, Member 2/metabolism
- Transfection
Collapse
|
|
24
|
Wei X, Sun H, Yan H, Zhang C, Zhang S, Liu X, Hua N, Ma X, Zheng J. ZC88, a novel 4-amino piperidine analog, inhibits the growth of neuroblastoma cells through blocking hERG potassium channel. Cancer Biol Ther 2014; 14:450-7. [PMID: 23917377 DOI: 10.4161/cbt.24423] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Many studies have provided convincing evidence for hERG as an important diagnostic and prognostic factor in human cancers, as well as a useful target for antineoplastic therapy. Our previous study also revealed that knockdown of herg gene expression by shRNA interference inhibited the growth of neuroblastoma cells in vitro and in vivo. In the experiment, a novel 4-amino piperidine analog, ZC88, was examined for its effect on hERG potassium channels and its antitumor potency was observed in vitro and in vivo. The results showed that ZC88 could block hERG1 and hERG1b channels expressed in Xenopus oocytes in a concentration-dependent manner. ZC88 displayed significant antiproliferative activity in several tumor cell lines and the tumor cells with higher expression of hERG presented higher sensitivity to ZC88. The mitotic progression of tumor cells was markedly suppressed in the presence of ZC88 through arresting cells in G₀/G₁ phase. ZC88 significantly inhibited the tumor growth in nude mice at a dosage with slight influence on the cardiac QT interval. The antitumor effect of ZC88 was correlated at least partly with its blockage of hERG channels, which implicated a positive role of hERG potassium channel in tumor cell proliferation.
Collapse
Affiliation(s)
- Xiaoli Wei
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Crociani O, Lastraioli E, Boni L, Pillozzi S, Romoli MR, D'Amico M, Stefanini M, Crescioli S, Masi A, Taddei A, Bencini L, Bernini M, Farsi M, Beghelli S, Scarpa A, Messerini L, Tomezzoli A, Vindigni C, Morgagni P, Saragoni L, Giommoni E, Gasperoni S, Di Costanzo F, Roviello F, De Manzoni G, Bechi P, Arcangeli A. hERG1 channels regulate VEGF-A secretion in human gastric cancer: clinicopathological correlations and therapeutical implications. Clin Cancer Res 2014; 20:1502-1512. [PMID: 24449824 DOI: 10.1158/1078-0432.ccr-13-2633] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
PURPOSE hERG1 channels are aberrantly expressed in several types of human cancers, where they affect different aspects of cancer cell behavior. A thorough analysis of the functional role and clinical significance of hERG1 channels in gastric cancer is still lacking. EXPERIMENTAL DESIGN hERG1 expression was tested in a wide (508 samples) Italian cohort of surgically resected patients with gastric cancer, by immunohistochemistry and real-time quantitative PCR. The functional link between hERG1 and the VEGF-A was studied in different gastric cancer cell lines. The effects of hERG1 and VEGF-A inhibition were evaluated in vivo in xenograft mouse models. RESULTS hERG1 was positive in 69% of the patients and positivity correlated with Lauren's intestinal type, fundus localization of the tumor, G1-G2 grading, I and II tumor-node-metastasis stage, and VEGF-A expression. hERG1 activity modulated VEGF-A secretion, through an AKT-dependent regulation of the transcriptional activity of the hypoxia inducible factor. Treatment of immunodeficient mice xenografted with human gastric cancer cells, with a combination of hERG1 blockers and anti-VEGF-A antibodies, impaired tumor growth more than single-drug treatments. CONCLUSION Our results show that hERG1 (i) is aberrantly expressed in human gastric cancer since its early stages; (ii) drives an intracellular pathway leading to VEGF-A secretion; (iii) can be exploited to identify a gastric cancer patients' group where a combined treatment with antiangiogenic drugs and noncardiotoxic hERG1 inhibitors could be proposed.
Collapse
Affiliation(s)
- Olivia Crociani
- Authors' Affiliations: Department of Clinical and Experimental Medicine; Surgery and Translational Medicine, University of Florence; Clinical Trials Coordinating Center; General Surgery and Surgical Oncology; Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence; Department of Pathology and Diagnostics, Division of Surgery, University of Verona; Pathology Division, Borgo Trento Hospital, Verona; Pathology Division, Azienda Ospedaliero-Universitaria Senese, Department of General Surgery and Oncology, University of Siena, Siena; and General Surgery and Division of Pathology, Morgagni-Pierantoni Hospital, Forlì, Italy
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Abstract
Potassium channels are transmembrane proteins that selectively facilitate the flow of potassium ions down an electrochemical gradient. These molecules have been studied in great detail in the context of cell excitability, but their roles in less cell type-specific functions, such as cell proliferation, angiogenesis or cell migration, have only recently been assessed. Moreover, the importance of these channels for tumour biology has become evident. This, coupled with the fact that they are accessible proteins and that their pharmacology is well characterized, has increased the interest in investigating potassium channels as therapeutic targets in cancer patients.
Collapse
Affiliation(s)
- Luis A Pardo
- Oncophysiology Group, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075 Göttingen, Germany
| | - Walter Stühmer
- Department of Molecular Biology of Neuronal Signals, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075 Göttingen, Germany
| |
Collapse
|
|
27
|
Zhang J, Zhao Z, Zu C, Hu H, Shen H, Zhang M, Wang J. Atrial natriuretic peptide modulates the proliferation of human gastric cancer cells via KCNQ1 expression. Oncol Lett 2013; 6:407-414. [PMID: 24137337 PMCID: PMC3789098 DOI: 10.3892/ol.2013.1425] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Accepted: 05/24/2013] [Indexed: 01/12/2023] Open
Abstract
Atrial natriuretic peptide (ANP) and brain NP (BNP) belong to the NP family that regulates mammalian blood volume and blood pressure. ANP signaling through NP receptor A (NPR-A)/cyclic guanosine 3′5′-monophosphate (cGMP)/ cGMP-dependent protein kinase (PKG) activates various downstream effectors involved in cell growth, apoptosis, proliferation and inflammation. Evidence has shown the critical role of plasma K+ channels in the regulation of tumor cell proliferation. However, the role of ANP in the proliferation of gastric cancer cells is not clear. In the present study, the expression of NPR-A in the human gastric cancer cell line, AGS, and the effect of ANP on the proliferation of AGS cells were investigated using western blotting, immunofluorescence, qPCR and patch clamp assays. The K+ current was also analyzed in the effect of ANP on the proliferation of AGS cells. NPR-A was expressed in the human gastric cancer AGS cell line. Lower concentrations of ANP promoted the proliferation of the AGS cells, although higher concentrations decreased their proliferation. Significant increases in the levels of cGMP activity were observed in the AGS cells treated with 10−10, 10−9 and 10−8 M ANP compared with the controls, but no significant differences were observed in the 10−7 and 10−6 M ANP groups. The patch clamp results showed that 10−9 M ANP significantly increased the tetraethylammonium (TEA)- and 293B-sensitive K+ current, while 10−6 M ANP significantly decreased the TEA- and 293B-sensitive K+ current. The results showed that 10−10 and 10−9 M ANP significantly upregulated the expression of potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) at the protein and mRNA levels, although 10−7 and 10−6 M ANP significantly downregulated the expression of KCNQ1. The data indicated that lower and higher concentrations of ANP have opposite effects on the proliferation of AGS cells through cGMP-dependent or -independent pathways. KCNQ1 upregulation and downregulation by lower and higher concentrations of ANP, respectively, have separate effects on the promotion and inhibition of proliferation.
Collapse
Affiliation(s)
- Jia Zhang
- Department of Surgical Oncology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | | | | | | | | | | | | |
Collapse
|
|
28
|
Role of HERG1 potassium channel in both malignant transformation and disease progression in head and neck carcinomas. Mod Pathol 2012; 25:1069-78. [PMID: 22460808 DOI: 10.1038/modpathol.2012.63] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Evidence indicates that human ether à-go-go-related gene 1 (HERG1) voltage-gated potassium channels could represent new valuable membrane therapeutic targets and diagnostic/prognostic biomarkers in various cancers. This study is the first to investigate the expression pattern of HERG1 potassium channel subunit in both primary tumors and precancerous lesions to establish its clinical and biological role during the development and progression of head and neck squamous cell carcinomas. HERG1 protein expression was evaluated by immunohistochemistry in paraffin-embedded tissue specimens from 133 patients with laryngeal/hypopharyngeal squamous cell carcinomas and 75 patients with laryngeal dysplasia, and correlated with clinical data. Our findings demonstrate that HERG1 is frequently aberrantly expressed in a high percentage of primary tumors (87%), whereas expression was negligible in both stromal cells and normal-adjacent epithelia. HERG1 expression increased during head and neck squamous cell carcinoma progression and was significantly associated with lymph node metastasis (P=0.04), advanced disease stages (P<0.001), regional tumor recurrence (P=0.004), distant metastasis (P=0.03) and reduced disease-specific survival (P=0.012, log-rank test). HERG1-positive expression was also detected in 31 (41%) of 75 laryngeal dysplasias. Interestingly, HERG1 expression increased with the grade of dysplasia; however, HERG1 expression but not histology correlated significantly with increased laryngeal cancer risk (P=0.007). In addition, functional studies in head and neck squamous cell carcinoma-derived cell lines further revealed that HERG1 expression promotes anchorage-dependent and -independent cell growth and invasive capability, although independently of its ion-conducting function. Our data demonstrate that HERG1 expression is a biologically and clinically relevant feature in head and neck squamous cell carcinoma progression and also during malignant transformation, and a promising candidate as cancer risk marker and therapeutic target for head and neck squamous cell carcinoma prevention and treatment.
Collapse
|
|
29
|
Immunohistochemical biomarkers in gastric cancer research and management. Int J Surg Oncol 2012; 2012:868645. [PMID: 22778942 PMCID: PMC3388584 DOI: 10.1155/2012/868645] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2012] [Revised: 04/22/2012] [Accepted: 04/25/2012] [Indexed: 12/25/2022] Open
Abstract
Gastric cancer still represents a major health problem, despite a decrease in its incidence in the last years. Due to the social impact of gastric cancer (GC), there is a need for novel biomarkers in order to stratify patients into appropriate screening, surveillance, or treatment programs. Although histopathology remains the most reliable and less expensive method, numerous efforts have been made searching for novel biomarkers. In recent years, several molecules have been identified and tested for their clinical relevance in GC management. In this paper, we will focus on a well-known GC marker, whose determination is mandatory in GC, HER2, a marker whose correlation with prognosis is still controversial (VEGF-A) and a quite novel, unconventional marker, the ether-à-go-go-related gene 1 (hERG1). All these proteins can be easily detected with immunohistochemistry, a technique widely used both in diagnostic and research laboratories that represents a link between surgical and molecular pathology, basic science, and clinical medicine.
Collapse
|
|
30
|
Glassmeier G, Hempel K, Wulfsen I, Bauer CK, Schumacher U, Schwarz JR. Inhibition of HERG1 K+ channel protein expression decreases cell proliferation of human small cell lung cancer cells. Pflugers Arch 2011; 463:365-76. [PMID: 22075718 PMCID: PMC3261411 DOI: 10.1007/s00424-011-1045-z] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2011] [Revised: 10/12/2011] [Accepted: 10/14/2011] [Indexed: 01/30/2023]
Abstract
HERG (human ether-à-go-go-related gene) K+ currents fulfill important ionic functions in cardiac and other excitable cells. In addition, HERG channels influence cell growth and migration in various types of tumor cells. The mechanisms underlying these functions are still not resolved. Here, we investigated the role of HERG channels for cell growth in a cell line (SW2) derived from small cell lung cancer (SCLC), a malignant variant of lung cancer. The two HERG1 isoforms (HERG1a, HERG1b) as well as HERG2 and HERG3 are expressed in SW2 cells. Inhibition of HERG currents by acute or sustained application of E-4031, a specific ERG channel blocker, depolarized SW2 cells by 10–15 mV. This result indicated that HERG K+ conductance contributes considerably to the maintenance of the resting potential of about −45 mV. Blockage of HERG channels by E-4031 for up to 72 h did not affect cell proliferation. In contrast, siRNA-induced inhibition of HERG1 protein expression decreased cell proliferation by about 50%. Reduction of HERG1 protein expression was confirmed by Western blots. HERG current was almost absent in SW2 cells transfected with siRNA against HERG1. Qualitatively similar results were obtained in three other SCLC cell lines (OH1, OH3, H82), suggesting that the HERG1 channel protein is involved in SCLC cell growth, whereas the ion-conducting function of HERG1 seems not to be important for cell growth.
Collapse
Affiliation(s)
- Günter Glassmeier
- Institut für Zelluläre und Integrative Physiologie, Universitätsklinikum Hamburg-Eppendorf, Universität Hamburg, Martinistr. 52, D-20246, Hamburg, Germany
| | | | | | | | | | | |
Collapse
|
|
31
|
Abstract
The human ether-a-go-go-related gene potassium channel (hERG, Kv11.1, KCNH2) has an essential role in cardiac action potential repolarization. Electrical dysfunction of the voltage-sensitive ion channel is associated with potentially lethal ventricular arrhythmias in humans. hERG K+ channels are also expressed in a variety of cancer cells where they control cell proliferation and apoptosis. In this review, we discuss molecular mechanisms of hERG-associated cell cycle regulation and cell death. In addition, the significance of hERG K+ channels as future drug target in anticancer therapy is highlighted.
Collapse
|
|
32
|
Shiozaki A, Otsuji E, Marunaka Y. Intracellular chloride regulates the G 1/S cell cycle progression in gastric cancer cells. World J Gastrointest Oncol 2011; 3:119-22. [PMID: 22007274 PMCID: PMC3192220 DOI: 10.4251/wjgo.v3.i8.119] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2011] [Revised: 07/25/2011] [Accepted: 08/01/2011] [Indexed: 02/05/2023] Open
Abstract
Recent studies show that ion channels/transporters play important roles in fundamental cellular functions. Several reports indicating the important roles of Cl- channels/transporters on cell proliferation suggest that the intracellular chloride concentration ([Cl-]i) regulated by them would be one of critical messengers. We investigated whether the [Cl-]i controls cell proliferation and cell cycle progression in human gastric cancer cells. Our studies indicated that furosemide, a blocker of Na+/K+/2Cl- cotransporter (NKCC), diminished cell growth by delaying the G1-S phase progression in gastric cancer cells with high expression and activity of NKCC. Furthermore, we found that the culture in the low Cl- medium (replacement of Cl- by NO3-) decreased the [Cl-]i and inhibited cell growth of gastric cancer cells and that this inhibition of cell growth was due to cell cycle arrest at the G0/G1 phase caused by diminution of CDK2 and phosphorylated Rb. The culture of cells in the low Cl- medium significantly increased expressions of p21 mRNA and protein. In addition, the low Cl- medium induced phosphorylation of mitogen activated protein kinases (MAPKs). Treatment with an inhibitor of p38 or JNK significantly suppressed p21 upregulation caused by culture in a low Cl- medium and rescued gastric cancer cells from the low Cl--induced G1 cell cycle arrest. These findings revealed that the [Cl-]i affects the cell proliferation via activation of MAPKs through upregulation of p21 in gastric cancer cells. Our results suggest that the [Cl-]i regulates important cellular functions in gastric cancer cells, leading to the development of novel therapeutic strategies.
Collapse
Affiliation(s)
- Atsushi Shiozaki
- Atsushi Shiozaki, Eigo Otsuji, Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | | | | |
Collapse
|
|
33
|
Abstract
Ion channels are involved in a variety of tumors. In particular, potassium channels are expressed abnormally in many cancer types, where their pharmacologic manipulation impairs tumor progression. Since this group of molecules has been successfully targeted for decades in other therapeutic areas, there is a significant body of knowledge on the pharmacology of potassium channels. Several groups of potassium channels with defined molecular identities have been proposed as candidates for therapeutic intervention. The strategies put forward range from classical small molecule blockade to gene therapy approaches, and include the use of potassium channels as targets for adjuvant therapy. We will discuss the reasons for these proposals and explore possible future developments.
Collapse
|
|
34
|
Wang Y, Zhang Y, Yang L, Cai B, Li J, Zhou Y, Yin L, Yang L, Yang BF, Lu YJ. Arsenic trioxide induces the apoptosis of human breast cancer MCF-7 cells through activation of caspase-3 and inhibition of HERG channels. Exp Ther Med 2011; 2:481-486. [PMID: 22977528 DOI: 10.3892/etm.2011.224] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2010] [Accepted: 02/28/2011] [Indexed: 01/27/2023] Open
Abstract
Arsenic trioxide (As(2)O(3)) has been widely used to treat patients with acute promyelocytic leukemia and has also been shown to exhibit therapeutic effects on various types of solid tumors, including gastric cancer and lung carcinoma. Breast cancer is a type of solid tumor whose incidence has been increasing for many years. The present study was designed to investigate the effects of As(2)O(3) on the human breast cancer cell line MCF-7, and to explore its potential mechanisms. The MTT assay demonstrated that As(2)O(3) decreased the cellular viability of MCF-7 cells in a concentration-dependent manner. Morphological observation, the TUNEL assay and flow cytometric analysis revealed that apoptosis was involved in the process. An assay for caspase-3 activity suggested that the apoptosis was mediated through caspase-3 activation. Further investigation indicated that protein levels of the human ether-a-go-go-related gene (HERG) were markedly downregulated by As(2)O(3). Taken together, the results indicate that arsenic trioxide induces the apoptosis of human breast cancer MCF-7 cells at least in part through the activation of caspase-3 and the decrease in HERG expression.
Collapse
Affiliation(s)
- Ying Wang
- Department of Pharmacology, State-Province Key Laboratories of Biomedicine and Pharmaceutics, and
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Asher V, Sowter H, Shaw R, Bali A, Khan R. Eag and HERG potassium channels as novel therapeutic targets in cancer. World J Surg Oncol 2010; 8:113. [PMID: 21190577 PMCID: PMC3022597 DOI: 10.1186/1477-7819-8-113] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2010] [Accepted: 12/29/2010] [Indexed: 12/03/2022] Open
Abstract
Voltage gated potassium channels have been extensively studied in relation to cancer. In this review, we will focus on the role of two potassium channels, Ether à-go-go (Eag), Human ether à-go-go related gene (HERG), in cancer and their potential therapeutic utility in the treatment of cancer. Eag and HERG are expressed in cancers of various organs and have been implicated in cell cycle progression and proliferation of cancer cells. Inhibition of these channels has been shown to reduce proliferation both in vitro and vivo studies identifying potassium channel modulators as putative inhibitors of tumour progression. Eag channels in view of their restricted expression in normal tissue may emerge as novel tumour biomarkers.
Collapse
Affiliation(s)
- Viren Asher
- Department of Obstetrics and Gynaecology, School of Graduate Medicine and Health, Royal Derby Hospital, Uttoxeter road, Derby DE22 3DT, UK.
| | | | | | | | | |
Collapse
|
|
36
|
Roepke TK, Purtell K, King EC, La Perle KMD, Lerner DJ, Abbott GW. Targeted deletion of Kcne2 causes gastritis cystica profunda and gastric neoplasia. PLoS One 2010; 5:e11451. [PMID: 20625512 PMCID: PMC2897890 DOI: 10.1371/journal.pone.0011451] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2010] [Accepted: 06/13/2010] [Indexed: 01/02/2023] Open
Abstract
Gastric cancer is the second leading cause of cancer death worldwide. Predisposing factors include achlorhydria, Helicobacter pylori infection, oxyntic atrophy and TFF2-expressing metaplasia. In parietal cells, apical potassium channels comprising the KCNQ1 α subunit and the KCNE2 β subunit provide a K+ efflux current to facilitate gastric acid secretion by the apical H+K+ATPase. Accordingly, genetic deletion of murine Kcnq1 or Kcne2 impairs gastric acid secretion. Other evidence has suggested a role for KCNE2 in human gastric cancer cell proliferation, independent of its role in gastric acidification. Here, we demonstrate that 1-year-old Kcne2−/− mice in a pathogen-free environment all exhibit a severe gastric preneoplastic phenotype comprising gastritis cystica profunda, 6-fold increased stomach mass, increased Ki67 and nuclear Cyclin D1 expression, and TFF2- and cytokeratin 7-expressing metaplasia. Some Kcne2−/−mice also exhibited pyloric polypoid adenomas extending into the duodenum, and neoplastic invasion of thin walled vessels in the sub-mucosa. Finally, analysis of human gastric cancer tissue indicated reduced parietal cell KCNE2 expression. Together with previous findings, the results suggest KCNE2 disruption as a possible risk factor for gastric neoplasia.
Collapse
Affiliation(s)
- Torsten K. Roepke
- Department of Pharmacology, Weill Medical College of Cornell University, New York, New York, United States of America
- Department of Medicine, Weill Medical College of Cornell University, New York, New York, United States of America
| | - Kerry Purtell
- Department of Pharmacology, Weill Medical College of Cornell University, New York, New York, United States of America
| | - Elizabeth C. King
- Department of Pharmacology, Weill Medical College of Cornell University, New York, New York, United States of America
| | - Krista M. D. La Perle
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Daniel J. Lerner
- Department of Medicine, Weill Medical College of Cornell University, New York, New York, United States of America
| | - Geoffrey W. Abbott
- Department of Pharmacology, Weill Medical College of Cornell University, New York, New York, United States of America
- Department of Medicine, Weill Medical College of Cornell University, New York, New York, United States of America
- * E-mail:
| |
Collapse
|
|
37
|
Role of ERG1 isoforms in modulation of ERG1 channel trafficking and function. Pflugers Arch 2010; 460:803-12. [DOI: 10.1007/s00424-010-0855-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2010] [Revised: 06/13/2010] [Accepted: 06/14/2010] [Indexed: 01/31/2023]
|
|
38
|
Arcangeli A, Becchetti A. New Trends in Cancer Therapy: Targeting Ion Channels and Transporters. Pharmaceuticals (Basel) 2010; 3:1202-1224. [PMID: 27713296 PMCID: PMC4034029 DOI: 10.3390/ph3041202] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2010] [Revised: 03/25/2010] [Accepted: 03/29/2010] [Indexed: 02/07/2023] Open
Abstract
The expression and activity of different channel types mark and regulate specific stages of cancer establishment and progression. Blocking channel activity impairs the growth of some tumors, both in vitro and in vivo, which opens a new field for pharmaceutical research. However, ion channel blockers may produce serious side effects, such as cardiac arrhythmias. For instance, Kv11.1 (hERG1) channels are aberrantly expressed in several human cancers, in which they control different aspects of the neoplastic cell behaviour. hERG1 blockers tend to inhibit cancer growth. However they also retard the cardiac repolarization, thus lengthening the electrocardiographic QT interval, which can lead to life-threatening ventricular arrhythmias. Several possibilities exist to produce less harmful compounds, such as developing specific drugs that bind hERG1 channels in the open state or disassemble the ion channel/integrin complex which appears to be crucial in certain stages of neoplastic progression. The potential approaches to improve the efficacy and safety of ion channel targeting in oncology include: (1) targeting specific conformational channel states; (2) finding ever more specific inhibitors, including peptide toxins, for channel subtypes mainly expressed in well-identified tumors; (3) using specific ligands to convey traceable or cytotoxic compounds; (4) developing channel blocking antibodies; (5) designing new molecular tools to decrease channel expression in selected cancer types. Similar concepts apply to ion transporters such as the Na⁺/K⁺ pump and the Na⁺/H⁺ exchanger. Pharmacological targeting of these transporters is also currently being considered in anti-neoplastic therapy.
Collapse
Affiliation(s)
- Annarosa Arcangeli
- Department of Experimental Pathology and Oncology, University of Florence, Italy.
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Italy.
| | - Andrea Becchetti
- Department of Experimental Pathology and Oncology, University of Florence, Italy
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Italy
| |
Collapse
|
|
39
|
Ding XW, Yang WB, Gao S, Wang W, Li Z, Hu WM, Li JJ, Luo HS. Prognostic significance of hERG1 expression in gastric cancer. Dig Dis Sci 2010; 55:1004-10. [PMID: 19495974 DOI: 10.1007/s10620-009-0834-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2008] [Accepted: 04/30/2009] [Indexed: 01/12/2023]
Abstract
Previous studies have demonstrated that human ether-à-go-go-related potassium channel (hERG1) is highly expressed in many tumor cell lines, as well as in primary human cancers, and, hence, have a critical role in cell cycle progress and proliferation. In this study, hERG1 expression was investigated in gastric cancer by immunohistochemistry and/or reverse transcription polymerase chain reaction (RT-PCR). It was discovered that hERG1, which was negatively expressed in surrounding non-tumor tissues, switched to aberrantly positive expression in gastric cancer. Statistically, there were significant differences in hERG1 protein expression according to factors such as serosal invasion, venous invasion, lymph node metastases, other organ metastases, and stage. The mean survival time for the hERG1-positive expression group was significantly shorter than the negative group, the survival rates for the positive group were significantly lower than the negative group, and hERG1 expression was found to be an independent prognostic factor. In summary, hERG1 channel was proved to be a potential biomarker for gastric cancer invasion and survival.
Collapse
Affiliation(s)
- Xiang-Wu Ding
- Department of Gastroenterology, Xiangfan Central Hospital, Xiangfan, 441021, People's Republic of China.
| | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Physical and Functional Interaction between Integrins and hERG1 Channels in Cancer Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2010; 674:55-67. [DOI: 10.1007/978-1-4419-6066-5_6] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
|
|
41
|
Cui G, Shu W, Wu Q, Chen Y. Effect of Gambogic acid on the regulation of hERG channel in K562 cells in vitro. ACTA ACUST UNITED AC 2009; 29:540-5. [DOI: 10.1007/s11596-009-0503-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2008] [Indexed: 02/07/2023]
|
|
42
|
Wu K, Nie Y, Guo C, Chen Y, Ding J, Fan D. Molecular basis of therapeutic approaches to gastric cancer. J Gastroenterol Hepatol 2009; 24:37-41. [PMID: 19196394 DOI: 10.1111/j.1440-1746.2008.05753.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Gastric cancer is the top lethal cancer in Asia. As the majority of cases present with advanced disease, conventional therapies (surgery, chemotherapy, and radiotherapy) have limited efficacy to reduce mortality. Emerging modalities provide promise to combat this malignancy. Target-protein-based cancer therapy has become available in clinical practice. Numerous molecules have been shown potential to target specific pathways for tumor cell growth. Cyclooxygenase-2 (COX-2) is overexpressed in and correlated with gastric cancer, and knockdown of COX-2 or administration of COX-2 inhibitors suppresses tumor formation in models of gastric cancer. Induction of apoptosis, reduction of angiogenesis, and blocking of potassium ion channels may present new mechanisms of COX-2 inhibition. Runt-related transcription factor 3 (RUNX3) is a candidate tumor suppressor gene whose deficiency is causally related to gastric cancer. RUNX3 is downregulated in metastatic gastric cancer. RUNX3 activation inhibits angiogenesis in xenograft tumors in nude mice. Tumor microenvironment modulation also provides a powerful tool to inhibit cancer development and progress; details of the potential roles of angiopoietins are discussed in this review. Osteopontin is a secreted protein involved in stress response, inflammation, wound healing, and immune response. Inhibition of osteopontin by RNA interfering technique suppressed tumorigenesis as well as angiogenesis in gastric cancer. Immunotherapy remains another important choice of adjuvant therapy for cancer. A tumor-specific antigen MG7-Ag has been identified with great potential for inducing immune response in gastric cancer. Using HLA-A-matched allogeneic gastric cancer cells to induce tumor-specific cytotoxic T lymphocytes appeared to be an alternative option of immunotherapy for gastric cancer.
Collapse
Affiliation(s)
- Kaichun Wu
- State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
| | | | | | | | | | | |
Collapse
|
|
43
|
Heitzmann D, Warth R. Physiology and pathophysiology of potassium channels in gastrointestinal epithelia. Physiol Rev 2008; 88:1119-82. [PMID: 18626068 DOI: 10.1152/physrev.00020.2007] [Citation(s) in RCA: 107] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Epithelial cells of the gastrointestinal tract are an important barrier between the "milieu interne" and the luminal content of the gut. They perform transport of nutrients, salts, and water, which is essential for the maintenance of body homeostasis. In these epithelia, a variety of K(+) channels are expressed, allowing adaptation to different needs. This review provides an overview of the current literature that has led to a better understanding of the multifaceted function of gastrointestinal K(+) channels, thereby shedding light on pathophysiological implications of impaired channel function. For instance, in gastric mucosa, K(+) channel function is a prerequisite for acid secretion of parietal cells. In epithelial cells of small intestine, K(+) channels provide the driving force for electrogenic transport processes across the plasma membrane, and they are involved in cell volume regulation. Fine tuning of salt and water transport and of K(+) homeostasis occurs in colonic epithelia cells, where K(+) channels are involved in secretory and reabsorptive processes. Furthermore, there is growing evidence for changes in epithelial K(+) channel expression during cell proliferation, differentiation, apoptosis, and, under pathological conditions, carcinogenesis. In the future, integrative approaches using functional and postgenomic/proteomic techniques will help us to gain comprehensive insights into the role of K(+) channels of the gastrointestinal tract.
Collapse
Affiliation(s)
- Dirk Heitzmann
- Institute of Physiology and Clinic and Policlinic for Internal Medicine II, Regensburg, Germany
| | | |
Collapse
|
|
44
|
|
|
45
|
Raschi E, Vasina V, Poluzzi E, De Ponti F. The hERG K+ channel: target and antitarget strategies in drug development. Pharmacol Res 2008; 57:181-195. [PMID: 18329284 DOI: 10.1016/j.phrs.2008.01.009] [Citation(s) in RCA: 112] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2007] [Revised: 01/21/2008] [Accepted: 01/22/2008] [Indexed: 12/16/2022]
Abstract
The human ether-à-go-go related gene (hERG) K+ channel is of great interest for both basic researchers and clinicians because its blockade by drugs can lead to QT prolongation, which is a risk factor for torsades de pointes, a potentially life-threatening arrhythmia. A growing list of agents with "QT liability" have been withdrawn from the market or restricted in their use, whereas others did not even receive regulatory approval for this reason. Thus, hERG K+ channels have become a primary antitarget (i.e. an unwanted target) in drug development because their blockade causes potentially serious side effects. On the other hand, the recent identification and functional characterization of hERG K+ channels not only in the heart, but also in several other tissues (e.g. neurons, smooth muscle and cancer cells) may have far reaching implications for drug development for a possible exploitation of hERG as a target, especially in oncology and cardiology.
Collapse
Affiliation(s)
- Emanuel Raschi
- Department of Pharmacology, University of Bologna, Via Irnerio, 48, I-40126 Bologna BO, Bologna, Italy
| | | | | | | |
Collapse
|
|
46
|
Lan M, Shi Y, Sun L, Liu L, Guo X, Lu Y, Wang J, Liang J, Fan D. KCl Depolarization Increases HIF-1 Transcriptional Activity via the Calcium-Independent Pathway in SGC7901 Gastric Cancer Cells. Tumour Biol 2007; 28:173-80. [PMID: 17519536 DOI: 10.1159/000103011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2006] [Accepted: 02/01/2007] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Hypoxia-inducible factor 1alpha (HIF-1alpha) has been reported to be expressed aberrantly in gastric cancer cells. Stability and transactivation of HIF-1 were associated with the change of intracellular calcium. We hypothesized that KCl depolarization may modulate HIF-1 activity in gastric cancer cells through calcium involvement. METHODS HIF-1alpha expression and its transcriptional activity were determined in SGC7901 gastric cancer cells treated with KCl and/or CoCl2 under normoxia. KCl induced change in the intracellular free calcium concentration and its effect on HIF-1 activity was investigated subsequently. RESULTS Exposure of SGC7901 cells to KCl (50 mM) could induce HIF-1alpha expression and its nucleus accumulation under normoxic conditions, reaching the peak at 8 and 2 h, respectively. KCl could also induce transactivation of the HIF-1 reporter gene and its target gene VEGF secretion at 8 h. Further experiments confirmed that depolarization of SGC7901 cells with KCl caused an increase in intracellular free calcium concentration. Chelation of intracellular calcium by BAPTA [1,2-bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid] induced HIF-1alpha accumulation and HIF-1 activity. However, elevation of cytosolic calcium level by ionomycin, a calcium ionophore, failed to induce HIF-1 transcriptional activity. CONCLUSIONS KCl depolarization would act through the calcium-independent pathway leading to enhanced HIF-1 transcriptional activity in gastric cancer cells.
Collapse
Affiliation(s)
- Mei Lan
- State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Yanglin P, Lina Z, Zhiguo L, Na L, Haifeng J, Guoyun Z, Jie L, Jun W, Tao L, Li S, Taidong Q, Jianhong W, Daiming F. KCNE2, a down-regulated gene identified by in silico analysis, suppressed proliferation of gastric cancer cells. Cancer Lett 2006; 246:129-38. [PMID: 16677757 DOI: 10.1016/j.canlet.2006.02.010] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2005] [Revised: 01/20/2006] [Accepted: 02/13/2006] [Indexed: 12/22/2022]
Abstract
It is important to identify the differentially expressed gene in gastric cancer for elucidating the molecular mechanisms of tumorigenesis of stomach. Here, 38 genes differentially expressed genes between gastric cancer and normal gastric mucosa by in silico approaches. A potassium channel protein KCNE2, identified as a down-regulated gene in gastric cancer, was chosen for further study. We investigated the expression of KCNE2 in gastric cancer tissues and cell lines and examined the effect of KCNE2 on proliferation of gastric cancer. The expression of KCNE2 was markedly down-regulated in gastric cancer tissues and cell lines. Forced overexpression of KCNE2 suppressed the growth of SGC7901 cells and cell cycle progression significantly, which might be related to the down-regulation of Cyclin D1. KCNE2 also inhibited SGC7901 cell growth in soft agar and its tumorigenicity in nude mice. Taken together, our work showed that in silico analysis approaches could be used to identify cancer-related genes effectively. KCNE2, as a novel down-regulated gene in gastric cancer, suppressed cell proliferation and tumorigenesis of stomach.
Collapse
Affiliation(s)
- Pan Yanglin
- State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi Province, PR China
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Shiozaki A, Miyazaki H, Niisato N, Nakahari T, Iwasaki Y, Itoi H, Ueda Y, Yamagishi H, Marunaka Y. Furosemide, a Blocker of Na+/K+/2Cl− Cotransporter, Diminishes Proliferation of Poorly Differentiated Human Gastric Cancer Cells by Affecting G0/G1 State. J Physiol Sci 2006; 56:401-6. [PMID: 17052386 DOI: 10.2170/physiolsci.rp010806] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2006] [Accepted: 10/18/2006] [Indexed: 12/17/2022]
Abstract
Furosemide, a blocker of Na(+)/K(+)/2Cl(-) cotransporter (NKCC), is often used as a diuretic to improve edema, ascites, and pleural effusion of patients with cancers. The aim of the present study was to investigate whether an NKCC blocker affects cancer cell growth. If so, we would clarify the mechanism of this action. We found that poorly differentiated gastric adenocarcinoma cells (MKN45) expressed the mRNA of NKCC1 three times higher than moderately differentiated ones (MKN28) and that the NKCC in MKN45 showed higher activity than that in MKN28. A cell proliferation assay indicates that furosemide significantly inhibited cell growth in MKN45 cells, but not in MKN28 cells. Using flow cytometrical analysis, we found that the exposure to furosemide brought MKN45 cells to spend more time at the G(0)/G(1) phase, but not MKN28 cells. Based on these observations, we indicate that furosemide diminishes cell growth by delaying the G(1)-S phase progression in poorly differentiated gastric adenocarcinoma cells, which show high expression and activity of NKCC, but not in moderately differentiated gastric adenocarcinoma cells with low expression and NKCC activity.
Collapse
Affiliation(s)
- Atsushi Shiozaki
- Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566 Japan
| | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Schönherr R. Clinical Relevance of Ion Channels for Diagnosis and Therapy of Cancer. J Membr Biol 2005; 205:175-84. [PMID: 16362505 DOI: 10.1007/s00232-005-0782-3] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2005] [Indexed: 12/29/2022]
Abstract
Ion channels have a critical role in cell proliferation and it is well documented that channel blockers can inhibit the growth of cancer cells. The concept of ion channels as therapeutic targets or prognostic biomarkers attracts increasing interest, but the lack of potent and selective channel modulators has hampered a critical verification for many years. Today, the knowledge of human ion channel genes is almost complete and molecular correlates for many native currents have already been identified. This information triggered a wave of experimental results, identifying individual ion channels with relevance for specific cancer types. The current pattern of cancer-related ion channels is not arbitrary, but can be reduced to few members from each ion channel family. This review aims to provide an overview of the molecularly identified ion channels that might be relevant for the most common human cancer types. Possible applications of these candidates for a targeted cancer therapy or for clinical diagnosis are discussed.
Collapse
Affiliation(s)
- R Schönherr
- Research Unit Molecular and Cellular Biophysics, Medical Faculty of the Friedrich Schiller University Jena, Drackendorfer St. 1, Jena, D-07747, Germany.
| |
Collapse
|