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Crizotinib Inhibits Hyperpolarization-activated Cyclic Nucleotide-Gated Channel 4 Activity
Sinus bradycardia is frequently observed in patients treated with crizotinib, a receptor tyrosine kinase inhibitor used for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We investigated whether crizotinib could influence heart rate (HR) through dire...
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| Published in: | Cardio-oncology (London, England) England), 2017, Vol.3 (1), p.1, Article 1 |
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| container_title | Cardio-oncology (London, England) |
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| creator | Zhang, Zhushan Huang, Tai-Qin Nepliouev, Igor Zhang, Hengtao Barnett, Adam S Rosenberg, Paul B Ou, Sai-Hong I Stiber, Jonathan A |
| description | Sinus bradycardia is frequently observed in patients treated with crizotinib, a receptor tyrosine kinase inhibitor used for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We investigated whether crizotinib could influence heart rate (HR) through direct cardiac effects.
The direct effect of crizotinib on HR was studied using ECG analysis of Langendorff-perfused mouse hearts. The whole-cell patch clamp technique was used to measure the effects of crizotinib on the hyperpolarization-activated funny current, I
, in mouse sinoatrial node cells (SANCs) and hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) activity in HEK-293 cells stably expressing human HCN4.
Crizotinib resulted in a dose-dependent reduction in HR in isolated intact mouse hearts with a half maximal inhibitory concentration (IC50) of 1.7 ± 0.4 μmol/L. Because ECG analysis revealed that crizotinib (0-5 μmol/L) resulted in significant reductions in HR in isolated mouse hearts without changes in PR, QRS, or QT intervals, we performed whole-cell patch clamp recordings of SANCs which showed that crizotinib inhibited I
which regulates cardiac pacemaker activity. Crizotinib resulted in diminished current density of HCN4, the major molecular determinant of I
, with an IC50 of 1.4 ± 0.3 μmol/L. Crizotinib also slowed HCN4 activation and shifted the activation curve to the left towards more hyperpolarized potentials.
Our results suggest that crizotinib's effects on HCN4 channels play a significant role in mediating its observed effects on HR. |
| doi_str_mv | 10.1186/s40959-017-0020-z |
| format | article |
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The direct effect of crizotinib on HR was studied using ECG analysis of Langendorff-perfused mouse hearts. The whole-cell patch clamp technique was used to measure the effects of crizotinib on the hyperpolarization-activated funny current, I
, in mouse sinoatrial node cells (SANCs) and hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) activity in HEK-293 cells stably expressing human HCN4.
Crizotinib resulted in a dose-dependent reduction in HR in isolated intact mouse hearts with a half maximal inhibitory concentration (IC50) of 1.7 ± 0.4 μmol/L. Because ECG analysis revealed that crizotinib (0-5 μmol/L) resulted in significant reductions in HR in isolated mouse hearts without changes in PR, QRS, or QT intervals, we performed whole-cell patch clamp recordings of SANCs which showed that crizotinib inhibited I
which regulates cardiac pacemaker activity. Crizotinib resulted in diminished current density of HCN4, the major molecular determinant of I
, with an IC50 of 1.4 ± 0.3 μmol/L. Crizotinib also slowed HCN4 activation and shifted the activation curve to the left towards more hyperpolarized potentials.
Our results suggest that crizotinib's effects on HCN4 channels play a significant role in mediating its observed effects on HR.</description><identifier>ISSN: 2057-3804</identifier><identifier>EISSN: 2057-3804</identifier><identifier>DOI: 10.1186/s40959-017-0020-z</identifier><identifier>PMID: 28217366</identifier><language>eng</language><publisher>England: BioMed Central</publisher><subject>Cardiac arrhythmia ; Clinical trials ; Electrocardiography ; Experiments ; Glucose ; Heart rate ; Laboratory animals ; Lung cancer ; Ostomy ; Sinuses ; Targeted cancer therapy</subject><ispartof>Cardio-oncology (London, England), 2017, Vol.3 (1), p.1, Article 1</ispartof><rights>2017. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s). 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c342z-5e1ba088c64729967a91341d2226d113a9459ebbbe163e75e1725cc71d2890623</citedby><cites>FETCH-LOGICAL-c342z-5e1ba088c64729967a91341d2226d113a9459ebbbe163e75e1725cc71d2890623</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310672/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2347751330?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,4043,25783,27956,27957,27958,37047,37048,44625,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28217366$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Zhushan</creatorcontrib><creatorcontrib>Huang, Tai-Qin</creatorcontrib><creatorcontrib>Nepliouev, Igor</creatorcontrib><creatorcontrib>Zhang, Hengtao</creatorcontrib><creatorcontrib>Barnett, Adam S</creatorcontrib><creatorcontrib>Rosenberg, Paul B</creatorcontrib><creatorcontrib>Ou, Sai-Hong I</creatorcontrib><creatorcontrib>Stiber, Jonathan A</creatorcontrib><title>Crizotinib Inhibits Hyperpolarization-activated Cyclic Nucleotide-Gated Channel 4 Activity</title><title>Cardio-oncology (London, England)</title><addtitle>Cardiooncology</addtitle><description>Sinus bradycardia is frequently observed in patients treated with crizotinib, a receptor tyrosine kinase inhibitor used for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We investigated whether crizotinib could influence heart rate (HR) through direct cardiac effects.
The direct effect of crizotinib on HR was studied using ECG analysis of Langendorff-perfused mouse hearts. The whole-cell patch clamp technique was used to measure the effects of crizotinib on the hyperpolarization-activated funny current, I
, in mouse sinoatrial node cells (SANCs) and hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) activity in HEK-293 cells stably expressing human HCN4.
Crizotinib resulted in a dose-dependent reduction in HR in isolated intact mouse hearts with a half maximal inhibitory concentration (IC50) of 1.7 ± 0.4 μmol/L. Because ECG analysis revealed that crizotinib (0-5 μmol/L) resulted in significant reductions in HR in isolated mouse hearts without changes in PR, QRS, or QT intervals, we performed whole-cell patch clamp recordings of SANCs which showed that crizotinib inhibited I
which regulates cardiac pacemaker activity. Crizotinib resulted in diminished current density of HCN4, the major molecular determinant of I
, with an IC50 of 1.4 ± 0.3 μmol/L. Crizotinib also slowed HCN4 activation and shifted the activation curve to the left towards more hyperpolarized potentials.
Our results suggest that crizotinib's effects on HCN4 channels play a significant role in mediating its observed effects on HR.</description><subject>Cardiac arrhythmia</subject><subject>Clinical trials</subject><subject>Electrocardiography</subject><subject>Experiments</subject><subject>Glucose</subject><subject>Heart rate</subject><subject>Laboratory animals</subject><subject>Lung cancer</subject><subject>Ostomy</subject><subject>Sinuses</subject><subject>Targeted cancer therapy</subject><issn>2057-3804</issn><issn>2057-3804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><recordid>eNpdkU9LAzEQxYMoWqofwIssePESzb9NshehFLVC0YtevIRsNrUp26Qmu0L76U1pFfU0w8zvPWZ4AJxjdI2x5DeJoaqsIMICIkQQ3ByAAUGlgFQidvirPwFnKS1QhghjnPNjcEIkwYJyPgBv4-g2oXPe1cWjn7vadamYrFc2rkKr8053LnioTec-dWebYrw2rTPFU29am3WNhQ-7-Vx7b9uCFaMt67r1KTia6TbZs30dgtf7u5fxBE6fHx7Hoyk0lJENLC2uNZLScCZIVXGhK0wZbgghvMGY6oqVla3r2mJOrci4IKUxIhOyQpzQIbjd-a76emkbY30XdatW0S11XKugnfq78W6u3sOnKilGXGwNrvYGMXz0NnVq6ZKxbau9DX1SWAqUj-NSZvTyH7oIffT5PUUoE6LElKJM4R1lYkgp2tnPMRipbXhqF57K4alteGqTNRe_v_hRfEdFvwCoUZVE</recordid><startdate>2017</startdate><enddate>2017</enddate><creator>Zhang, Zhushan</creator><creator>Huang, Tai-Qin</creator><creator>Nepliouev, Igor</creator><creator>Zhang, Hengtao</creator><creator>Barnett, Adam S</creator><creator>Rosenberg, Paul B</creator><creator>Ou, Sai-Hong I</creator><creator>Stiber, Jonathan A</creator><general>BioMed Central</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>2017</creationdate><title>Crizotinib Inhibits Hyperpolarization-activated Cyclic Nucleotide-Gated Channel 4 Activity</title><author>Zhang, Zhushan ; Huang, Tai-Qin ; Nepliouev, Igor ; Zhang, Hengtao ; Barnett, Adam S ; Rosenberg, Paul B ; Ou, Sai-Hong I ; Stiber, Jonathan A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c342z-5e1ba088c64729967a91341d2226d113a9459ebbbe163e75e1725cc71d2890623</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Cardiac arrhythmia</topic><topic>Clinical trials</topic><topic>Electrocardiography</topic><topic>Experiments</topic><topic>Glucose</topic><topic>Heart rate</topic><topic>Laboratory animals</topic><topic>Lung cancer</topic><topic>Ostomy</topic><topic>Sinuses</topic><topic>Targeted cancer therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Zhushan</creatorcontrib><creatorcontrib>Huang, Tai-Qin</creatorcontrib><creatorcontrib>Nepliouev, Igor</creatorcontrib><creatorcontrib>Zhang, Hengtao</creatorcontrib><creatorcontrib>Barnett, Adam S</creatorcontrib><creatorcontrib>Rosenberg, Paul B</creatorcontrib><creatorcontrib>Ou, Sai-Hong I</creatorcontrib><creatorcontrib>Stiber, Jonathan A</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cardio-oncology (London, England)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Zhushan</au><au>Huang, Tai-Qin</au><au>Nepliouev, Igor</au><au>Zhang, Hengtao</au><au>Barnett, Adam S</au><au>Rosenberg, Paul B</au><au>Ou, Sai-Hong I</au><au>Stiber, Jonathan A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Crizotinib Inhibits Hyperpolarization-activated Cyclic Nucleotide-Gated Channel 4 Activity</atitle><jtitle>Cardio-oncology (London, England)</jtitle><addtitle>Cardiooncology</addtitle><date>2017</date><risdate>2017</risdate><volume>3</volume><issue>1</issue><spage>1</spage><pages>1-</pages><artnum>1</artnum><issn>2057-3804</issn><eissn>2057-3804</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Sinus bradycardia is frequently observed in patients treated with crizotinib, a receptor tyrosine kinase inhibitor used for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We investigated whether crizotinib could influence heart rate (HR) through direct cardiac effects.
The direct effect of crizotinib on HR was studied using ECG analysis of Langendorff-perfused mouse hearts. The whole-cell patch clamp technique was used to measure the effects of crizotinib on the hyperpolarization-activated funny current, I
, in mouse sinoatrial node cells (SANCs) and hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) activity in HEK-293 cells stably expressing human HCN4.
Crizotinib resulted in a dose-dependent reduction in HR in isolated intact mouse hearts with a half maximal inhibitory concentration (IC50) of 1.7 ± 0.4 μmol/L. Because ECG analysis revealed that crizotinib (0-5 μmol/L) resulted in significant reductions in HR in isolated mouse hearts without changes in PR, QRS, or QT intervals, we performed whole-cell patch clamp recordings of SANCs which showed that crizotinib inhibited I
which regulates cardiac pacemaker activity. Crizotinib resulted in diminished current density of HCN4, the major molecular determinant of I
, with an IC50 of 1.4 ± 0.3 μmol/L. Crizotinib also slowed HCN4 activation and shifted the activation curve to the left towards more hyperpolarized potentials.
Our results suggest that crizotinib's effects on HCN4 channels play a significant role in mediating its observed effects on HR.</abstract><cop>England</cop><pub>BioMed Central</pub><pmid>28217366</pmid><doi>10.1186/s40959-017-0020-z</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | Cardio-oncology (London, England), 2017, Vol.3 (1), p.1, Article 1 |
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| language | eng |
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| source | Publicly Available Content Database; PubMed Central |
| subjects | Cardiac arrhythmia Clinical trials Electrocardiography Experiments Glucose Heart rate Laboratory animals Lung cancer Ostomy Sinuses Targeted cancer therapy |
| title | Crizotinib Inhibits Hyperpolarization-activated Cyclic Nucleotide-Gated Channel 4 Activity |
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