{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T03:46:12Z","timestamp":1777520772952,"version":"3.51.4"},"reference-count":48,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2019,12,4]],"date-time":"2019-12-04T00:00:00Z","timestamp":1575417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"publisher","award":["HI18C0263"],"award-info":[{"award-number":["HI18C0263"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002619","name":"Ajou University","doi-asserted-by":"publisher","award":["The 2019 MD PhD research fund of Ajou University School of Medicine"],"award-info":[{"award-number":["The 2019 MD PhD research fund of Ajou University School of Medicine"]}],"id":[{"id":"10.13039\/501100002619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The proteasome inhibitor (PI), bortezomib (Btz), is effective in treating multiple myeloma and mantle cell lymphoma, but not solid tumors. In this study, we show for the first time that lercanidipine (Ler), an antihypertensive drug, enhances the cytotoxicity of various PIs, including Btz, carfilzomib, and ixazomib, in many solid tumor cell lines by inducing paraptosis, which is accompanied by severe vacuolation derived from the endoplasmic reticulum (ER) and mitochondria. We found that Ler potentiates Btz-mediated ER stress and ER dilation, possibly due to misfolded protein accumulation, in MDA-MB 435S cells. In addition, the combination of Btz and Ler triggers mitochondrial Ca2+ overload, critically contributing to mitochondrial dilation and subsequent paraptotic events, including mitochondrial membrane potential loss and ER dilation. Taken together, our results suggest that a combined regimen of PI and Ler may effectively kill cancer cells via structural and functional perturbations of the ER and mitochondria.<\/jats:p>","DOI":"10.3390\/ijms20246112","type":"journal-article","created":{"date-parts":[[2019,12,5]],"date-time":"2019-12-05T03:16:36Z","timestamp":1575515796000},"page":"6112","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Lercanidipine Synergistically Enhances Bortezomib Cytotoxicity in Cancer Cells via Enhanced Endoplasmic Reticulum Stress and Mitochondrial Ca2+ Overload"],"prefix":"10.3390","volume":"20","author":[{"given":"A Reum","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Ajou University, Suwon 16499, Korea"},{"name":"Department of Biomedical Science, Ajou University Graduate School of Medicine, Suwon 16499, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min Ji","family":"Seo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Ajou University, Suwon 16499, Korea"},{"name":"Department of Biomedical Science, Ajou University Graduate School of Medicine, Suwon 16499, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Ajou University, Suwon 16499, Korea"},{"name":"Department of Biomedical Science, Ajou University Graduate School of Medicine, Suwon 16499, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong Min","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Ajou University, Suwon 16499, Korea"},{"name":"Department of Biomedical Science, Ajou University Graduate School of Medicine, Suwon 16499, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"In Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Ajou University, Suwon 16499, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mi Jin","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Ajou University, Suwon 16499, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hur","family":"Hoon","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Ajou University Graduate School of Medicine, Suwon 16499, Korea"},{"name":"Department of Surgery, Ajou University School of Medicine, Suwon 16499, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyeong Sook","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Ajou University, Suwon 16499, Korea"},{"name":"Department of Biomedical Science, Ajou University Graduate School of Medicine, Suwon 16499, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1007\/s10555-017-9707-8","article-title":"The proteasome and proteasome inhibitors in multiple myeloma","volume":"36","author":"Gandolfi","year":"2017","journal-title":"Cancer Metastasis Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.trsl.2018.03.002","article-title":"Next-generation proteasome inhibitors for cancer therapy","volume":"198","author":"Park","year":"2018","journal-title":"Transl. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.2217\/fon.14.30","article-title":"Efficacy of therapy with bortezomib in solid tumors: A review based on 32 clinical trials","volume":"10","author":"Huang","year":"2014","journal-title":"Future Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1007\/s00280-013-2267-x","article-title":"A phase I\/II study of carfilzomib 2-10-min infusion in patients with advanced solid tumors","volume":"72","author":"Papadopoulos","year":"2013","journal-title":"Cancer Chemother Pharm."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"242","DOI":"10.2174\/187152011795255948","article-title":"The ubiquitin+proteasome protein degradation pathway as a therapeutic strategy in the treatment of solid tumor malignancies","volume":"11","author":"Driscoll","year":"2011","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/s00280-017-3489-0","article-title":"Positioning of proteasome inhibitors in therapy of solid malignancies","volume":"81","author":"Roeten","year":"2018","journal-title":"Cancer Chemother Pharm."},{"key":"ref_7","first-page":"6","article-title":"Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead","volume":"44","author":"Shah","year":"2019","journal-title":"J. Clin. Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1517\/17425250903085135","article-title":"Treatment of essential hypertension with calcium channel blockers: What is the place of lercanidipine?","volume":"5","author":"Burnier","year":"2009","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.2165\/00003495-200363220-00013","article-title":"Lercanidipine: A review of its efficacy in the management of hypertension","volume":"63","author":"Bang","year":"2003","journal-title":"Drugs"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.2147\/VHRM.S3510","article-title":"Patient adherence and the choice of antihypertensive drugs: Focus on lercanidipine","volume":"4","author":"Pruijm","year":"2008","journal-title":"Vasc. Health Risk Manag."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.1001\/jama.291.20.2441","article-title":"Prognostic importance of comorbidity in a hospital-based cancer registry","volume":"291","author":"Piccirillo","year":"2004","journal-title":"JAMA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1080\/14779072.2017.1409114","article-title":"Cardiovascular complications of multiple myeloma in the elderly","volume":"15","author":"Mathur","year":"2017","journal-title":"Expert Rev. Cardiovasc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1586\/erc.12.155","article-title":"Role of dihydropyridinic calcium channel blockers in the management of hypertension","volume":"11","author":"Coca","year":"2013","journal-title":"Expert Rev. Cardiovasc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.ejphar.2014.10.058","article-title":"Cytotoxic and multidrug resistance reversal activities of novel 1,4-dihydropyridines against human cancer cells","volume":"746","author":"Shekari","year":"2015","journal-title":"Eur. J. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1007\/s10637-009-9340-7","article-title":"Inhibition of MDR1 activity and induction of apoptosis by analogues of nifedipine and diltiazem: An in vitro analysis","volume":"29","author":"Viale","year":"2011","journal-title":"Investig. New Drugs"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"14376","DOI":"10.1073\/pnas.97.26.14376","article-title":"An alternative, nonapoptotic form of programmed cell death","volume":"97","author":"Sperandio","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1038\/sj.cdd.4401465","article-title":"Paraptosis: Mediation by MAP kinases and inhibition by AIP-1\/Alix","volume":"11","author":"Sperandio","year":"2004","journal-title":"Cell Death Differ."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.pharmthera.2016.01.003","article-title":"Paraptosis in the anti-cancer arsenal of natural products","volume":"162","author":"Lee","year":"2016","journal-title":"Pharmacol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e1112","DOI":"10.1038\/cddis.2014.85","article-title":"Stronger proteasomal inhibition and higher CHOP induction are responsible for more effective induction of paraptosis by dimethoxycurcumin than curcumin","volume":"5","author":"Yoon","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.yexcr.2018.02.018","article-title":"6-Shogaol induces caspase-independent paraptosis in cancer cells via proteasomal inhibition","volume":"364","author":"Nedungadi","year":"2018","journal-title":"Exp. Cell Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/j.freeradbiomed.2009.12.016","article-title":"Superoxide anion and proteasomal dysfunction contribute to curcumin-induced paraptosis of malignant breast cancer cells","volume":"48","author":"Yoon","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.canlet.2012.05.018","article-title":"Simultaneous mitochondrial Ca2+ overload and proteasomal inhibition are responsible for the induction of paraptosis in malignant breast cancer cells","volume":"324","author":"Yoon","year":"2012","journal-title":"Cancer Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6816","DOI":"10.18632\/oncotarget.2256","article-title":"Release of Ca2+ from the endoplasmic reticulum and its subsequent influx into mitochondria trigger celastrol-induced paraptosis in cancer cells","volume":"5","author":"Yoon","year":"2014","journal-title":"Oncotarget"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e365","DOI":"10.1038\/emm.2017.112","article-title":"Nutlin-3 enhances the bortezomib sensitivity of p53-defective cancer cells by inducing paraptosis","volume":"49","author":"Lee","year":"2017","journal-title":"Exp. Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.cbi.2018.02.003","article-title":"Morusin induces paraptosis-like cell death through mitochondrial calcium overload and dysfunction in epithelial ovarian cancer","volume":"283","author":"Xue","year":"2018","journal-title":"Chem. Biol. Interact."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"513","DOI":"10.2353\/ajpath.2007.070188","article-title":"Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability","volume":"171","author":"Ding","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.bbrc.2014.04.142","article-title":"Molecular control of mitochondrial calcium uptake","volume":"449","author":"Rizzuto","year":"2014","journal-title":"Biochem. Biophys Res. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1016\/j.bbamcr.2015.04.008","article-title":"Structure and function of the mitochondrial calcium uniporter complex","volume":"1853","author":"Patron","year":"2015","journal-title":"Biochim. Biophys Acta"},{"key":"ref_29","first-page":"252","article-title":"Mitochondrial regulation of intracellular Ca2+ signaling: More than just simple Ca2+ buffers","volume":"18","author":"Parekh","year":"2003","journal-title":"News Physiol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.ceca.2010.02.001","article-title":"Intracellular Ca2+ storage in health and disease: A dynamic equilibrium","volume":"47","author":"Sammels","year":"2010","journal-title":"Cell Calcium."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1517\/13543784.8.7.1043","article-title":"Lercanidipine: A novel lipophilic dihydropyridine calcium antagonist with long duration of action and high vascular selectivity","volume":"8","author":"Meredith","year":"1999","journal-title":"Expert. Opin. Investig. Drugs"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1211\/0022357991772844","article-title":"Vascular-selective effect of lercanidipine and other 1,4-dihydropyridines in isolated rabbit tissues","volume":"51","author":"Angelico","year":"1999","journal-title":"J. Pharm. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1517\/14656566.8.14.2215","article-title":"Efficacy and tolerability of lercanidipine in patients with hypertension: Results of a Phase IV study in general practice","volume":"8","author":"Burnier","year":"2007","journal-title":"Expert Opin. Pharm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1158\/1541-7786.MCR-06-0019","article-title":"Endoplasmic reticulum vacuolization and valosin-containing protein relocalization result from simultaneous hsp90 inhibition by geldanamycin and proteasome inhibition by velcade","volume":"4","author":"Mimnaugh","year":"2006","journal-title":"Mol. Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.ceca.2012.03.004","article-title":"The permeability transition pore as a Ca2+ release channel: New answers to an old question","volume":"52","author":"Bernardi","year":"2012","journal-title":"Cell Calcium."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"20796","DOI":"10.1074\/jbc.M109.025353","article-title":"Calcium elevation in mitochondria is the main Ca2+ requirement for mitochondrial permeability transition pore (mPTP) opening","volume":"284","author":"Baumgartner","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/sj.onc.1210638","article-title":"Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis","volume":"27","author":"Deniaud","year":"2008","journal-title":"Oncogene"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1016\/j.bbabio.2008.12.011","article-title":"Characteristics and possible functions of mitochondrial Ca(2+) transport mechanisms","volume":"1787","author":"Gunter","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1054\/ceca.1999.0061","article-title":"Permeability transition pore regulates both mitochondrial membrane potential and agonist-evoked Ca2+ signals in oligodendrocyte progenitors","volume":"26","author":"Smaili","year":"1999","journal-title":"Cell Calcium"},{"key":"ref_40","first-page":"H1699","article-title":"Cyclosporin inhibits mitochondrial calcium efflux in isolated adult rat ventricular cardiomyocytes","volume":"262","author":"Altschuld","year":"1992","journal-title":"Am. J. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1111\/j.1469-7793.2000.t01-1-00461.x","article-title":"Dihydropyridine-induced Ca2+ release from ryanodine-sensitive Ca2+pools in human skeletal muscle cells","volume":"525","author":"Weigl","year":"2000","journal-title":"J. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6027","DOI":"10.1113\/jphysiol.2012.237321","article-title":"Dihydropyridine receptors actively control gating of ryanodine receptors in resting mouse skeletal muscle fibres","volume":"590","author":"Robin","year":"2012","journal-title":"J. Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"d659","DOI":"10.2741\/dirksen","article-title":"Bi-directional coupling between dihydropyridine receptors and ryanodine receptors","volume":"7","author":"Dirksen","year":"2002","journal-title":"Front. Biosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"19006","DOI":"10.1074\/jbc.M109.011296","article-title":"Structural model for dihydropyridine binding to L-type calcium channels","volume":"284","author":"Tikhonov","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.bbadis.2009.12.005","article-title":"Calpains and proteasomes mediate degradation of ryanodine receptors in a model of cardiac ischemic reperfusion","volume":"1802","author":"Pedrozo","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s40262-018-0679-9","article-title":"Clinical Pharmacokinetics and Pharmacodynamics of Bortezomib","volume":"58","author":"Tan","year":"2019","journal-title":"Clin. Pharm."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1097\/00132580-200111000-00008","article-title":"Lercanidipine: A novel dihydropyridine calcium-channel blocker","volume":"3","author":"Epstein","year":"2001","journal-title":"Heart Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0065-2571(84)90007-4","article-title":"Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors","volume":"22","author":"Chou","year":"1984","journal-title":"Adv. Enzym. Regul."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/24\/6112\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:40:07Z","timestamp":1760190007000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/24\/6112"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,4]]},"references-count":48,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["ijms20246112"],"URL":"https:\/\/doi.org\/10.3390\/ijms20246112","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,4]]}}}