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Repurposing hyperpolarization-activated cyclic nucleotide-gated channels as a novel therapy for breast cancer.

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cam.issuedOnline2021-11-04
dc.contributor.authorMok, Ka-Chun
dc.contributor.authorTsoi, Ho
dc.contributor.authorMan, Ellen Ps
dc.contributor.authorLeung, Man-Hong
dc.contributor.authorChau, Ka Man
dc.contributor.authorWong, Lai-San
dc.contributor.authorChan, Wing-Lok
dc.contributor.authorChan, Sum-Yin
dc.contributor.authorLuk, Mai-Yee
dc.contributor.authorChan, Jessie YW
dc.contributor.authorLeung, Jackie KM
dc.contributor.authorChan, Yolanda HY
dc.contributor.authorBatalha, Sellma
dc.contributor.authorLau, Virginia
dc.contributor.authorSiu, David CW
dc.contributor.authorLee, Terence KW
dc.contributor.authorGong, Chun
dc.contributor.authorKhoo, Ui-Soon
dc.contributor.orcidKhoo, Ui-Soon [0000-0003-2200-7505]
dc.date.accessioned2021-11-04T10:20:03Z
dc.date.available2021-11-04T10:20:03Z
dc.date.issued2021-11
dc.date.submitted2021-04-14
dc.date.updated2021-11-04T10:20:02Z
dc.description.abstractHyperpolarization-activated cyclic nucleotide-gated (HCN) channels are members of the voltage-gated cation channel family known to be expressed in the heart and central nervous system. Ivabradine, a small molecule HCN channel-blocker, is FDA-approved for clinical use as a heart rate-reducing agent. We found that HCN2 and HCN3 are overexpressed in breast cancer cells compared with normal breast epithelia, and the high expression of HCN2 and HCN3 is associated with poorer survival in breast cancer patients. Inhibition of HCN by Ivabradine or by RNAi, aborted breast cancer cell proliferation in vitro and suppressed tumour growth in patient-derived tumour xenograft models established from triple-negative breast cancer (TNBC) tissues, with no evident side-effects on the mice. Transcriptome-wide analysis showed enrichment for cholesterol metabolism and biosynthesis as well as lipid metabolism pathways associated with ER-stress following Ivabradine treatment. Mechanistic studies confirmed that HCN inhibition leads to ER-stress, in part due to disturbed Ca2+ homeostasis, which subsequently triggered the apoptosis cascade. More importantly, we investigated the synergistic effect of Ivabradine and paclitaxel on TNBC and confirmed that both drugs acted synergistically in vitro through ER-stress to amplify signals for caspase activation. Combination therapy could suppress tumour growth of xenografts at much lower doses for both drugs. In summary, our study identified a new molecular target with potential for being developed into targeted therapy, providing scientific grounds for initiating clinical trials for a new treatment regimen of combining HCN inhibition with chemotherapy.
dc.identifier.doi10.17863/CAM.77721
dc.identifier.eissn2001-1326
dc.identifier.issn2001-1326
dc.identifier.otherctm2578
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/330280
dc.languageen
dc.language.isoeng
dc.publisherWiley
dc.publisher.urlhttp://dx.doi.org/10.1002/ctm2.578
dc.subjectER-stress
dc.subjectHCN
dc.subjectIvabradine
dc.subjecttargeted therapy
dc.subjecttriple-negative breast cancer
dc.subjectCell Line
dc.subjectFemale
dc.subjectHumans
dc.subjectHyperpolarization-Activated Cyclic Nucleotide-Gated Channels
dc.subjectIvabradine
dc.subjectTriple Negative Breast Neoplasms
dc.titleRepurposing hyperpolarization-activated cyclic nucleotide-gated channels as a novel therapy for breast cancer.
dc.typeArticle
dcterms.dateAccepted2021-09-06
prism.issueIdentifier11
prism.publicationNameClin Transl Med
prism.volume11
pubs.funder-project-idInnovation and Technology Commission, HKSAR (ITS/069/16)
pubs.funder-project-idHealth and Medical Research Fund, HKSAR (04151826, 07182026)
pubs.funder-project-idCommittee on Research and Conference Grants from the University of Hong Kong Project numbers (201511159217, 202010160029)
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1002/ctm2.578

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