{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T01:44:09Z","timestamp":1792374249759,"version":"4.4.0"},"reference-count":50,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,3,27]],"date-time":"2020-03-27T00:00:00Z","timestamp":1585267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2015M3A9C7030181"],"award-info":[{"award-number":["2015M3A9C7030181"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Drug resistance in epithelial ovarian cancer (EOC) is reportedly attributed to the existence of cancer stem cells (CSC), because in most cancers, CSCs still remain after chemotherapy. To overcome this limitation, novel therapeutic strategies are required to prevent cancer recurrence and chemotherapy-resistant cancers by targeting cancer stem cells (CSCs). We screened an FDA-approved compound library and found four voltage-gated calcium channel blockers (manidipine, lacidipine, benidipine, and lomerizine) that target ovarian CSCs. Four calcium channel blockers (CCBs) decreased sphere formation, viability, and proliferation, and induced apoptosis in ovarian CSCs. CCBs destroyed stemness and inhibited the AKT and ERK signaling pathway in ovarian CSCs. Among calcium channel subunit genes, three L- and T-type calcium channel genes were overexpressed in ovarian CSCs, and downregulation of calcium channel genes reduced the stem-cell-like properties of ovarian CSCs. Expressions of these three genes are negatively correlated with the survival rate of patient groups. In combination therapy with cisplatin, synergistic effect was shown in inhibiting the viability and proliferation of ovarian CSCs. Moreover, combinatorial usage of manidipine and paclitaxel showed enhanced effect in ovarian CSCs xenograft mouse models. Our results suggested that four CCBs may be potential therapeutic drugs for preventing ovarian cancer recurrence.<\/jats:p>","DOI":"10.3390\/ijms21072327","type":"journal-article","created":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T03:44:13Z","timestamp":1585712653000},"page":"2327","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Calcium Channels as Novel Therapeutic Targets for Ovarian Cancer Stem Cells"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8903-8520","authenticated-orcid":false,"given":"Heejin","family":"Lee","sequence":"first","affiliation":[{"name":"New Drug Development Center, DGMIF, 80 Chumbok-ro, Dong-gu, Daegu 41061, Korea"},{"name":"School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun Woo","family":"Kim","sequence":"additional","affiliation":[{"name":"New Drug Development Center, DGMIF, 80 Chumbok-ro, Dong-gu, Daegu 41061, Korea"},{"name":"School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dae Kyung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Kyu","family":"Choi","sequence":"additional","affiliation":[{"name":"New Drug Development Center, DGMIF, 80 Chumbok-ro, Dong-gu, Daegu 41061, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seul","family":"Lee","sequence":"additional","affiliation":[{"name":"New Drug Development Center, DGMIF, 80 Chumbok-ro, Dong-gu, Daegu 41061, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Hoon","family":"Yu","sequence":"additional","affiliation":[{"name":"New Drug Development Center, DGMIF, 80 Chumbok-ro, Dong-gu, Daegu 41061, Korea"},{"name":"School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oh-Bin","family":"Kwon","sequence":"additional","affiliation":[{"name":"New Drug Development Center, DGMIF, 80 Chumbok-ro, Dong-gu, Daegu 41061, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jungsul","family":"Lee","sequence":"additional","affiliation":[{"name":"3 billion Inc., Seocho-gu, Seoul 06621, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7106-1615","authenticated-orcid":false,"given":"Dong-Seok","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Ho","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Hyun","family":"Min","sequence":"additional","affiliation":[{"name":"New Drug Development Center, DGMIF, 80 Chumbok-ro, Dong-gu, Daegu 41061, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/S0029-6465(22)02813-4","article-title":"Ovarian cancer. The most lethal gynecologic malignancy","volume":"27","author":"Brucks","year":"1992","journal-title":"Nurs. Clin. North Am."},{"key":"ref_2","first-page":"823","article-title":"Epithelial ovarian cancer: A challenge in gynecologic oncology","volume":"39","author":"Dauplat","year":"1992","journal-title":"Pathol. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1186\/1476-4598-13-262","article-title":"Developing ovarian cancer stem cell models: Laying the pipeline from discovery to clinical intervention","volume":"13","author":"Ffrench","year":"2014","journal-title":"Mol. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1097\/MD.0000000000004764","article-title":"Cancer stem cells: Understanding tumor hierarchy and heterogeneity","volume":"95","author":"Rich","year":"2016","journal-title":"Medicine"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9339","DOI":"10.1158\/0008-5472.CAN-06-3126","article-title":"Cancer stem cells-perspectives on current status and future directions: AACR Workshop on cancer stem cells","volume":"66","author":"Clarke","year":"2006","journal-title":"Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"8665","DOI":"10.18632\/oncotarget.2356","article-title":"Induced cancer stem-like cells as a model for biological screening and discovery of agents targeting phenotypic traits of cancer stem cell","volume":"5","author":"Nishi","year":"2014","journal-title":"Oncotarget"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1038\/nrc2499","article-title":"Cancer stem cells in solid tumours: Accumulating evidence and unresolved questions","volume":"8","author":"Visvader","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1002\/path.2793","article-title":"Cancer stem cells: Problems for therapy?","volume":"223","author":"Alison","year":"2011","journal-title":"J. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nrc1590","article-title":"Tumour stem cells and drug resistance","volume":"5","author":"Dean","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1038\/ncb2308","article-title":"In vitro generation of human cells with cancer stem cell properties","volume":"13","author":"Scaffidi","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1007\/s11626-997-0048-8","article-title":"Growth requirements and neoplastic transformation of two types of normal human breast epithelial cells derived from reduction mammoplasty","volume":"33","author":"Kao","year":"1997","journal-title":"Cell Dev. Biol. Anim."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3983","DOI":"10.1073\/pnas.0530291100","article-title":"Prospective identification of tumorigenic breast cancer cells","volume":"100","author":"Wicha","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","first-page":"5821","article-title":"Identification of a cancer stem cell in human brain tumors","volume":"63","author":"Singh","year":"2003","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1158\/0008-5472.CAN-08-2741","article-title":"Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature","volume":"69","author":"Ginestier","year":"2009","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1016\/j.cell.2008.03.027","article-title":"The epithelial-mesenchymal transition generates cells with properties of stem cells","volume":"133","author":"Mani","year":"2008","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.cell.2009.06.034","article-title":"Identification of selective inhibitors of cancer stem cells by high-throughput screening","volume":"138","author":"Gupta","year":"2009","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1002\/stem.2279","article-title":"Autotaxin Regulates Maintenance of Ovarian Cancer Stem Cells through Lysophosphatidic Acid-Mediated Autocrine Mechanism","volume":"34","author":"Seo","year":"2016","journal-title":"Stem Cells"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.3892\/mmr.2014.2974","article-title":"Apigenin inhibits the self-renewal capacity of human ovarian cancer SKOV3derived sphere-forming cells","volume":"11","author":"Tang","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e255","DOI":"10.1038\/emm.2016.73","article-title":"Crucial role of HMGA1 in the self-renewal and drug resistance of ovarian cancer stem cells","volume":"48","author":"Kim","year":"2016","journal-title":"Exp. Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.3892\/mmr.2014.2012","article-title":"FOXO3a-mediated suppression of the self-renewal capacity of sphere-forming cells derived from the ovarian cancer SKOV3 cell line by 7-difluoromethoxyl-5,4\u2019-di-n-octyl genistein","volume":"9","author":"Ning","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1016\/j.bcp.2012.12.017","article-title":"Inhibition of T-type calcium channels disrupts Akt signaling and promotes apoptosis in glioblastoma cells","volume":"85","author":"Valerie","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/ajh.2007.13","article-title":"Calcium channel blockers suppress cytokine-induced activation of human neutrophils","volume":"21","author":"Shima","year":"2008","journal-title":"Am. J. Hypertens."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.bbrc.2012.06.128","article-title":"L-type calcium channels play a crucial role in the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells","volume":"424","author":"Wen","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.mce.2011.08.038","article-title":"Calcium signaling in pluripotent stem cells","volume":"353","author":"Erdei","year":"2012","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"40419","DOI":"10.1074\/jbc.M405079200","article-title":"Calcium restriction allows cAMP activation of the B-Raf\/ERK pathway, switching cells to a cAMP-dependent growth-stimulated phenotype","volume":"279","author":"Yamaguchi","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.ejmech.2016.01.012","article-title":"PI3K\/Akt\/mTOR and Ras\/Raf\/MEK\/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives","volume":"109","author":"Asati","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/sj.leu.2402824","article-title":"Involvement of PI3K\/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: A target for cancer chemotherapy","volume":"17","author":"Chang","year":"2003","journal-title":"Leukemia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1177\/1758834014544121","article-title":"Treatment options in recurrent ovarian cancer: Latest evidence and clinical potential","volume":"6","author":"Luvero","year":"2014","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/0471141755.ph1425s61","article-title":"Overview of cancer stem cells (CSCs) and mechanisms of their regulation: Implications for cancer therapy","volume":"61","author":"Bao","year":"2013","journal-title":"Curr. Protoc. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/nrclinonc.2017.44","article-title":"EMT, CSCs, and drug resistance: The mechanistic link and clinical implications","volume":"14","author":"Shibue","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1038\/nm.4409","article-title":"Cancer stem cells revisited","volume":"23","author":"Batlle","year":"2017","journal-title":"Nat. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"S20","DOI":"10.1097\/MD.0000000000004766","article-title":"Cancer stem cells: Role in tumor growth, recurrence, metastasis, and treatment resistance","volume":"95","author":"Chang","year":"2016","journal-title":"Medicine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/nrd1468","article-title":"Drug repositioning: Identifying and developing new uses for existing drugs","volume":"3","author":"Ashburn","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"110","DOI":"10.2174\/1874467208666150507105845","article-title":"Pharmacology of L-type Calcium Channels: Novel Drugs for Old Targets?","volume":"8","author":"Striessnig","year":"2015","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1007\/s00424-014-1454-x","article-title":"T-type calcium channel blockers as neuroprotective agents","volume":"466","author":"Kopecky","year":"2014","journal-title":"Pflugers Arch."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1111\/j.1527-3466.2004.tb00141.x","article-title":"Clinical potential of lomerizine, a Ca2+ channel blocker as an anti-glaucoma drug: Effects on ocular circulation and retinal neuronal damage","volume":"22","author":"Hara","year":"2004","journal-title":"Cardiovasc. Drug Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1158\/0008-5472.CAN-16-2274","article-title":"Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein\/Amino Acid Responses","volume":"77","author":"Niklasson","year":"2017","journal-title":"Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.ccr.2013.02.025","article-title":"1B50-1, a mAb raised against recurrent tumor cells, targets liver tumor-initiating cells by binding to the calcium channel alpha2delta1 subunit","volume":"23","author":"Zhao","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/aps.2013.27","article-title":"Understanding and targeting cancer stem cells: Therapeutic implications and challenges","volume":"34","author":"Chen","year":"2013","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.4252\/wjsc.v7.i9.1185","article-title":"Therapies targeting cancer stem cells: Current trends and future challenges","volume":"7","author":"Dragu","year":"2015","journal-title":"World J. Stem Cells"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1126\/science.1063395","article-title":"Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway","volume":"294","author":"Dolmetsch","year":"2001","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"G403","DOI":"10.1152\/ajpgi.00119.2007","article-title":"Wnt5a secretion stimulated by the extracellular calcium-sensing receptor inhibits defective Wnt signaling in colon cancer cells","volume":"293","author":"MacLeod","year":"2007","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Prieto-Vila, M., Takahashi, R.-U., Usuba, W., Kohama, I., and Ochiya, T. (2017). Drug Resistance Driven by Cancer Stem Cells and Their Niche. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18122574"},{"key":"ref_44","first-page":"340","article-title":"Targeting cancer stem cells: A new therapy to cure cancer patients","volume":"2","author":"Hu","year":"2012","journal-title":"Am. J. Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1093\/jnci\/djh095","article-title":"Cancer stem cells: Are we missing the target?","volume":"96","author":"Jones","year":"2004","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"280","DOI":"10.3322\/caac.21559","article-title":"Epithelial ovarian cancer: Evolution of management in the era of precision medicine","volume":"69","author":"Lheureux","year":"2019","journal-title":"CA Cancer J. Clin."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s13167-019-00175-0","article-title":"Identification of clinical trait-related lncRNA and mRNA biomarkers with weighted gene co-expression network analysis as useful tool for personalized medicine in ovarian cancer","volume":"10","author":"Li","year":"2019","journal-title":"EPMA J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s13167-019-00170-5","article-title":"Signaling pathway network alterations in human ovarian cancers identified with quantitative mitochondrial proteomics","volume":"10","author":"Li","year":"2019","journal-title":"EPMA J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s13167-018-0128-8","article-title":"The crucial role of multiomic approach in cancer research and clinically relevant outcomes","volume":"9","author":"Lu","year":"2018","journal-title":"EPMA J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/nrc.2016.25","article-title":"Targeting metastasis","volume":"16","author":"Steeg","year":"2016","journal-title":"Nat. Rev. Cancer"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/7\/2327\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:12:26Z","timestamp":1760173946000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/7\/2327"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,27]]},"references-count":50,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["ijms21072327"],"URL":"https:\/\/doi.org\/10.3390\/ijms21072327","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,27]]}}}