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

Abstract Hyperpolarization‐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‐reducin...

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Autores principales:	Ka‐Chun Mok, Ho Tsoi, Ellen PS Man, Man‐Hong Leung, Ka Man Chau, Lai‐San Wong, Wing‐Lok Chan, Sum‐Yin Chan, Mai‐Yee Luk, Jessie Y.W. Chan, Jackie K.M. Leung, Yolanda H.Y. Chan, Sellma Batalha, Virginia Lau, David C.W. Siu, Terence K.W. Lee, Chun Gong, Ui‐Soon Khoo
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	ER‐stress HCN Ivabradine targeted therapy triple‐negative breast cancer Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/89dc802a66c04d34bba35fe0b981b854
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spelling	oai:doaj.org-article:89dc802a66c04d34bba35fe0b981b8542021-11-30T07:25:38ZRepurposing hyperpolarization‐activated cyclic nucleotide‐gated channels as a novel therapy for breast cancer2001-132610.1002/ctm2.578https://doaj.org/article/89dc802a66c04d34bba35fe0b981b8542021-11-01T00:00:00Zhttps://doi.org/10.1002/ctm2.578https://doaj.org/toc/2001-1326Abstract Hyperpolarization‐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.Ka‐Chun MokHo TsoiEllen PS ManMan‐Hong LeungKa Man ChauLai‐San WongWing‐Lok ChanSum‐Yin ChanMai‐Yee LukJessie Y.W. ChanJackie K.M. LeungYolanda H.Y. ChanSellma BatalhaVirginia LauDavid C.W. SiuTerence K.W. LeeChun GongUi‐Soon KhooWileyarticleER‐stressHCNIvabradinetargeted therapytriple‐negative breast cancerMedicine (General)R5-920ENClinical and Translational Medicine, Vol 11, Iss 11, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ER‐stress HCN Ivabradine targeted therapy triple‐negative breast cancer Medicine (General) R5-920
spellingShingle	ER‐stress HCN Ivabradine targeted therapy triple‐negative breast cancer Medicine (General) R5-920 Ka‐Chun Mok Ho Tsoi Ellen PS Man Man‐Hong Leung Ka Man Chau Lai‐San Wong Wing‐Lok Chan Sum‐Yin Chan Mai‐Yee Luk Jessie Y.W. Chan Jackie K.M. Leung Yolanda H.Y. Chan Sellma Batalha Virginia Lau David C.W. Siu Terence K.W. Lee Chun Gong Ui‐Soon Khoo Repurposing hyperpolarization‐activated cyclic nucleotide‐gated channels as a novel therapy for breast cancer
description	Abstract Hyperpolarization‐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.
format	article
author	Ka‐Chun Mok Ho Tsoi Ellen PS Man Man‐Hong Leung Ka Man Chau Lai‐San Wong Wing‐Lok Chan Sum‐Yin Chan Mai‐Yee Luk Jessie Y.W. Chan Jackie K.M. Leung Yolanda H.Y. Chan Sellma Batalha Virginia Lau David C.W. Siu Terence K.W. Lee Chun Gong Ui‐Soon Khoo
author_facet	Ka‐Chun Mok Ho Tsoi Ellen PS Man Man‐Hong Leung Ka Man Chau Lai‐San Wong Wing‐Lok Chan Sum‐Yin Chan Mai‐Yee Luk Jessie Y.W. Chan Jackie K.M. Leung Yolanda H.Y. Chan Sellma Batalha Virginia Lau David C.W. Siu Terence K.W. Lee Chun Gong Ui‐Soon Khoo
author_sort	Ka‐Chun Mok
title	Repurposing hyperpolarization‐activated cyclic nucleotide‐gated channels as a novel therapy for breast cancer
title_short	Repurposing hyperpolarization‐activated cyclic nucleotide‐gated channels as a novel therapy for breast cancer
title_full	Repurposing hyperpolarization‐activated cyclic nucleotide‐gated channels as a novel therapy for breast cancer
title_fullStr	Repurposing hyperpolarization‐activated cyclic nucleotide‐gated channels as a novel therapy for breast cancer
title_full_unstemmed	Repurposing hyperpolarization‐activated cyclic nucleotide‐gated channels as a novel therapy for breast cancer
title_sort	repurposing hyperpolarization‐activated cyclic nucleotide‐gated channels as a novel therapy for breast cancer
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/89dc802a66c04d34bba35fe0b981b854
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Repurposing hyperpolarization‐activated cyclic nucleotide‐gated channels as a novel therapy for breast cancer

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