File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
  • Find via Find It@HKUL
Supplementary

Conference Paper: Hyperpolarization-activated cyclic nucleotide-gated channel (HCN) blocker, Ivabradine, a novel potential targeted treatment for triple-negative breast cancer.

TitleHyperpolarization-activated cyclic nucleotide-gated channel (HCN) blocker, Ivabradine, a novel potential targeted treatment for triple-negative breast cancer.
Authors
Issue Date2018
PublisherPergamon. The Journal's web site is located at http://www.elsevier.com/locate/ejca
Citation
30th EORTC-NCI-AACR Symposium: Molecular Targets and Cancer Therapeutics, Dublin, Ireland. 13-16 November 2018. In European Journal of Cancer, 2018, v. 103 n. Suppl. 1, p. e125 How to Cite?
AbstractBackground: Triple-negative breast cancer patients who cannot benefit from targeted therapies, receive chemotherapeutic agents with attendant side effects. Ivabradine is an FDA approved Hyperpolarization-activated cyclic nucleotide-gated channels (HCN 1–4) targeting therapeutic agent, used clinically to treat chronic angina. We found HCN2 and HCN3 overexpressed in breast cancer compared with low expression in normal breast, both from TCGA data, cell line samples and clinical tissue samples. Treatment with Ivabradine significantly suppressed proliferation of breast cancer cells. We hypothesized that Ivabradine may be used to preferentially target breast cancer. Materials and Methods: In-vitro functional assays using breast cancer cell-lines were used to characterize the mechanism of action of HCN channel inhibition on breast cancer cells. In-vivo mouse models using both breast cancer xenograft and patient derived tumor xenograft (PDTX) were also used to demonstrate the efficacy of Ivabradine treatment. Results: Subcellular fractionation experiments confirmed HCN2 and HCN3 were largely localized to the cell membrane. MCF-10A, MDA-MB-231, MDA-MB-453 and BT-474 cell-lines were treated with 200 μM Ivabradine, 40 nM Paclitaxel or 625 nM Doxorubicin. All 3 drugs caused reduced cell viability and proliferation, and induced apoptosis of breast cancer cells. In contrast, Ivabradine did not significantly alter cell viability, proliferation nor apoptosis of the normal breast epithelial cell line MCF-10A. Mechanistically, we found that Ivabradine treatment could deplete intracellular calcium ion concentration, induce ER stress, caspase-mediated apoptosis, autophagy and cell senescence. Breast cancer xenografts MDA-MB-231 and MDA-MB-453 treated with Ivabradine showed decreased tumor growth compared with control group. Knockdown of HCN2 and HCN3 showed similar results as that with Ivabradine treatment in vitro as well as for in vivo xenografts. Ivabradine treatment also effectively reduced tumor growth in 6 out of 8 PDTX models established so far of triple negative breast cancer, with no discernable side effects on the treated mice. Conclusions: Targeting HCN channels using Ivabradine can be an effective novel targeted therapy for triple negative breast cancer. Being a clinically approved drug, it can more readily pave the way for clinical trials. There is also potential to test the application of antibodies against HCN2 and HCN3 on PDTX and develop humanized antibodies for use as anti-cancer drugs.
DescriptionPoster Session - no. 385 (PB-048)
Persistent Identifierhttp://hdl.handle.net/10722/272072
ISSN
2019 Impact Factor: 7.275
2015 SCImago Journal Rankings: 3.152

 

DC FieldValueLanguage
dc.contributor.authorKhoo, US-
dc.contributor.authorMok, KC-
dc.contributor.authorTsoi, H-
dc.contributor.authorMan, PS-
dc.contributor.authorChau, KM-
dc.contributor.authorLee, TK-
dc.contributor.authorGong, C-
dc.date.accessioned2019-07-20T10:35:07Z-
dc.date.available2019-07-20T10:35:07Z-
dc.date.issued2018-
dc.identifier.citation30th EORTC-NCI-AACR Symposium: Molecular Targets and Cancer Therapeutics, Dublin, Ireland. 13-16 November 2018. In European Journal of Cancer, 2018, v. 103 n. Suppl. 1, p. e125-
dc.identifier.issn0959-8049-
dc.identifier.urihttp://hdl.handle.net/10722/272072-
dc.descriptionPoster Session - no. 385 (PB-048)-
dc.description.abstractBackground: Triple-negative breast cancer patients who cannot benefit from targeted therapies, receive chemotherapeutic agents with attendant side effects. Ivabradine is an FDA approved Hyperpolarization-activated cyclic nucleotide-gated channels (HCN 1–4) targeting therapeutic agent, used clinically to treat chronic angina. We found HCN2 and HCN3 overexpressed in breast cancer compared with low expression in normal breast, both from TCGA data, cell line samples and clinical tissue samples. Treatment with Ivabradine significantly suppressed proliferation of breast cancer cells. We hypothesized that Ivabradine may be used to preferentially target breast cancer. Materials and Methods: In-vitro functional assays using breast cancer cell-lines were used to characterize the mechanism of action of HCN channel inhibition on breast cancer cells. In-vivo mouse models using both breast cancer xenograft and patient derived tumor xenograft (PDTX) were also used to demonstrate the efficacy of Ivabradine treatment. Results: Subcellular fractionation experiments confirmed HCN2 and HCN3 were largely localized to the cell membrane. MCF-10A, MDA-MB-231, MDA-MB-453 and BT-474 cell-lines were treated with 200 μM Ivabradine, 40 nM Paclitaxel or 625 nM Doxorubicin. All 3 drugs caused reduced cell viability and proliferation, and induced apoptosis of breast cancer cells. In contrast, Ivabradine did not significantly alter cell viability, proliferation nor apoptosis of the normal breast epithelial cell line MCF-10A. Mechanistically, we found that Ivabradine treatment could deplete intracellular calcium ion concentration, induce ER stress, caspase-mediated apoptosis, autophagy and cell senescence. Breast cancer xenografts MDA-MB-231 and MDA-MB-453 treated with Ivabradine showed decreased tumor growth compared with control group. Knockdown of HCN2 and HCN3 showed similar results as that with Ivabradine treatment in vitro as well as for in vivo xenografts. Ivabradine treatment also effectively reduced tumor growth in 6 out of 8 PDTX models established so far of triple negative breast cancer, with no discernable side effects on the treated mice. Conclusions: Targeting HCN channels using Ivabradine can be an effective novel targeted therapy for triple negative breast cancer. Being a clinically approved drug, it can more readily pave the way for clinical trials. There is also potential to test the application of antibodies against HCN2 and HCN3 on PDTX and develop humanized antibodies for use as anti-cancer drugs.-
dc.languageeng-
dc.publisherPergamon. The Journal's web site is located at http://www.elsevier.com/locate/ejca-
dc.relation.ispartofEuropean Journal of Cancer-
dc.relation.ispartof30th EORTC-NCI-AACR Symposium-
dc.titleHyperpolarization-activated cyclic nucleotide-gated channel (HCN) blocker, Ivabradine, a novel potential targeted treatment for triple-negative breast cancer.-
dc.typeConference_Paper-
dc.identifier.emailKhoo, US: uskhoo@hku.hk-
dc.identifier.emailMan, PS: ellenman@hku.hk-
dc.identifier.authorityKhoo, US=rp00362-
dc.identifier.hkuros298380-
dc.identifier.volume103-
dc.identifier.issueSuppl. 1-
dc.identifier.spagee125-
dc.identifier.epagee125-
dc.publisher.placeUnited Kingdom-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats