ArticleAmerican journal of physiology. Cell physiology2009
State-dependent block of HERG potassium channels by R-roscovitine: implications for cancer therapy.
Article in American journal of physiology. Cell physiology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 52 citations in OpenAlex.
- Ion channels in lung cancer: biological and clinical relevance.Frontiers in pharmacology · 2023Review
- Targeting late ICaL to close the window to ventricular arrhythmias.The Journal of general physiology · 2021Article
- Suppression of ventricular arrhythmias by targeting late L-type Ca2+ current.The Journal of general physiology · 2021Article
- Article
- Preclinical study of a Kv11.1 potassium channel activator as antineoplastic approach for breast cancer.Oncotarget · 2018Article
- Inhibition of cloned hERG potassium channels by risperidone and paliperidone.Naunyn-Schmiedeberg's archives of pharmacology · 2017Article
- Acepromazine inhibits hERG potassium ion channels expressed in human embryonic kidney 293 cells.The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2017Article
- Voltage-gated ion channels in cancer cell proliferation.Cancers · 2015Review
- Role of ion channels in regulating Ca²⁺ homeostasis during the interplay between immune and cancer cells.Cell death & disease · 2015Review
- Roscovitine is a proteostasis regulator that corrects the trafficking defect of F508del-CFTR by a CDK-independent mechanism.British journal of pharmacology · 2014Article
- Escitalopram block of hERG potassium channels.Naunyn-Schmiedeberg's archives of pharmacology · 2014Article
- The roles of K(+) channels in cancer.Nature reviews. Cancer · 2014Review
- Identification of specific sensory neuron populations for study of expressed ion channels.Journal of visualized experiments : JoVE · 2013Article
- Identification of CaV channel types expressed in muscle afferent neurons.Journal of neurophysiology · 2013Article
- ZC88, a novel 4-amino piperidine analog, inhibits the growth of neuroblastoma cells through blocking hERG potassium channel.Cancer biology & therapy · 2013Article
- Roscovitine inhibits CaV3.1 (T-type) channels by preferentially affecting closed-state inactivation.The Journal of pharmacology and experimental therapeutics · 2012Article
- Imatinib mesylate decreases the cytotoxic effect of roscovitine on human glioblastoma cells in vitro and the role of midkine.Oncology letters · 2012Article
- Identification of human Ether-à-go-go related gene modulators by three screening platforms in an academic drug-discovery setting.Assay and drug development technologies · 2010Article
- Ceramide modulates HERG potassium channel gating by translocation into lipid rafts.American journal of physiology. Cell physiology · 2010Article
- New Trends in Cancer Therapy: Targeting Ion Channels and Transporters.Pharmaceuticals (Basel, Switzerland) · 2010Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Human ether-a-go-go-related gene (HERG) potassium channel acts as a delayed rectifier in cardiac myocytes and is an important target for both pro- and antiarrhythmic drugs. Many drugs have been pulled from the market for unintended HERG block causing arrhythmias. Conversely, recent evidence has shown that HERG plays a role in cell proliferation and is overexpressed both in multiple tumor cell lines and in primary tumor cells, which makes HERG an attractive target for cancer treatment. Therefore, a drug that can block HERG but that does not induce cardiac arrhythmias would have great therapeutic potential. Roscovitine is a cyclin-dependent kinase (CDK) inhibitor that is in phase II clinical trials as an anticancer agent. In the present study we show that R-roscovitine blocks HERG potassium current (human embryonic kidney-293 cells stably expressing HERG) at clinically relevant concentrations. The block (IC(50) = 27 microM) was rapid (tau = 20 ms) and reversible (tau = 25 ms) and increased with channel activation, which supports an open channel mechanism. Kinetic study of wild-type and inactivation mutant HERG channels supported block of activated channels by roscovitine with relatively little effect on either closed or inactivated channels. A HERG gating model reproduced all roscovitine effects. Our model of open channel block by roscovitine may offer an explanation of the lack of arrhythmias in clinical trials using roscovitine, which suggests the utility of a dual CDK/HERG channel block as an adjuvant cancer therapy.
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