{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T03:38:47Z","timestamp":1788406727279,"version":"build-2803163510"},"reference-count":38,"publisher":"Walter de Gruyter GmbH","issue":"1","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Oxaliplatin (OXA) is among the most common chemotherapy drugs and is the base component of the FOLFOX regimen (OXA + leucovorin + 5-fluorouracil) and CapeOX regimen (OXA + capecitabine). Resistance to and failure of these two OXA-based regimens often results in poor outcomes in patients with colorectal cancer (CRC). Nitrendipine (NTD) is a first-line antihypertensive drug commonly used in hypertension and coronary heart disease with confirmed low toxicity and side effects. However, the potential benefits of NTD for CRC progression and therapy remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Cell counting kit-8 (CCK-8) detection, colony formation assay, wound-healing assay, Transwell assay, SynergyFinder webtool, and subcutaneous tumor models were used to assess the effect of NTD with OXA on CRC inhibition\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      . Bioinformatics tools including Human Protein Atlas (HPA), quantitative real-time polymerase chain reaction, western blotting analyses, lentivirus transfection, and rescue experiment were used to investigate the mechanism(s) of the related action.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Utilizing murine and human CRC cell lines, the\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      experiment demonstrated that NTD inhibited cell proliferation, migration, and invasion, and the synergy scores calculated by SynergyFinder indicated that NTD exhibited synergistic activity with the chemotherapeutic drug OXA. The CCK-8 detection, animal model, and rescue experiment results demonstrated that NTD suppressed CRC progression and potentiated OXA therapeutic effect by downregulating calcium voltage-gated channel subunit alpha1 D (CACNA1D).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study presents novel data on first-line antihypertensive NTD, exerting inhibitory effects on cell proliferation and migration in CRC and revealing synergistic activity with OXA by downregulating CACNA1D. NTD may be a candidate as a promising chemosensitizer as an OXA new combination to improve the efficacy and safety of CRC therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1515\/med-2024-1138","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T17:48:41Z","timestamp":1739382521000},"source":"Crossref","is-referenced-by-count":3,"title":["The first-line antihypertensive nitrendipine potentiated the therapeutic effect of oxaliplatin by downregulating CACNA1D in colorectal cancer"],"prefix":"10.1515","volume":"20","author":[{"given":"Chengzhe","family":"Lai","sequence":"first","affiliation":[{"name":"Department of Cardiology, The Fourth Affiliated Hospital of Guangzhou Medical University , Zengcheng , Guangzhou , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Fourth Affiliated Hospital of Guangzhou Medical University , Zengcheng , Guangzhou , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingna","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Medicine, Taizhou University , Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haokun","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Fourth Affiliated Hospital of Guangzhou Medical University , Zengcheng , Guangzhou , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2025,2,12]]},"reference":[{"key":"2025122201304107141_j_med-2024-1138_ref_001","doi-asserted-by":"crossref","unstructured":"Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7\u201333.","DOI":"10.3322\/caac.21708"},{"key":"2025122201304107141_j_med-2024-1138_ref_002","doi-asserted-by":"crossref","unstructured":"Zhang C, Stampfl-Mattersberger M, Ruckser R, Sebesta C. Colorectal cancer. Wien Med Wochenschr. 2023;173(9\u201310):216\u201320.","DOI":"10.1007\/s10354-022-00975-6"},{"key":"2025122201304107141_j_med-2024-1138_ref_003","doi-asserted-by":"crossref","unstructured":"Shinji S, Yamada T, Matsuda A, Sonoda H, Ohta R, Iwai T, et al. Recent advances in the treatment of colorectal cancer: A review. J Nippon Med Sch. 2022;89(3):246\u201354.","DOI":"10.1272\/jnms.JNMS.2022_89-310"},{"key":"2025122201304107141_j_med-2024-1138_ref_004","doi-asserted-by":"crossref","unstructured":"Katona BW, Weiss JM. Chemoprevention of colorectal cancer. Gastroenterology. 2020;158(2):368\u201388.","DOI":"10.1053\/j.gastro.2019.06.047"},{"key":"2025122201304107141_j_med-2024-1138_ref_005","doi-asserted-by":"crossref","unstructured":"Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: A review. JAMA. 2021;325(7):669\u201385.","DOI":"10.1001\/jama.2021.0106"},{"key":"2025122201304107141_j_med-2024-1138_ref_006","doi-asserted-by":"crossref","unstructured":"Dekker E, Tanis PJ, Vleugels J, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394(10207):1467\u201380.","DOI":"10.1016\/S0140-6736(19)32319-0"},{"key":"2025122201304107141_j_med-2024-1138_ref_007","doi-asserted-by":"crossref","unstructured":"Mauri G, Gori V, Bonazzina E, Amatu A, Tosi F, Bencardino K, et al. Oxaliplatin retreatment in metastatic colorectal cancer: Systematic review and future research opportunities. Cancer treat rev. 2020;91:102112.","DOI":"10.1016\/j.ctrv.2020.102112"},{"key":"2025122201304107141_j_med-2024-1138_ref_008","doi-asserted-by":"crossref","unstructured":"Zhang X, Wu Q, Wei M, Deng X, Gu C, Wang Z. Oxaliplatin versus mitomycin C in HIPEC for peritoneal metastasis from colorectal cancer: a systematic review and meta-analysis of comparative studies. Int J Colorectal Dis. 2020;35(10):1831\u20139.","DOI":"10.1007\/s00384-020-03702-y"},{"key":"2025122201304107141_j_med-2024-1138_ref_009","doi-asserted-by":"crossref","unstructured":"Cremolini C, Antoniotti C, Rossini D, Lonardi S, Loupakis F, Pietrantonio F, et al. Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): A multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020;21(4):497\u2013507.","DOI":"10.2139\/ssrn.3478102"},{"key":"2025122201304107141_j_med-2024-1138_ref_010","doi-asserted-by":"crossref","unstructured":"Zhang C, Xu C, Gao X, Yao Q. Platinum-based drugs for cancer therapy and anti-tumor strategies. Theranostics. 2022;12(5):2115\u201332.","DOI":"10.7150\/thno.69424"},{"key":"2025122201304107141_j_med-2024-1138_ref_011","doi-asserted-by":"crossref","unstructured":"Vodenkova S, Buchler T, Cervena K, Veskrnova V, Vodicka P, Vymetalkova V. 5-fluorouracil and other fluoropyrimidines in colorectal cancer: Past, present and future. Pharmacol Ther. 2020;206:107447.","DOI":"10.1016\/j.pharmthera.2019.107447"},{"key":"2025122201304107141_j_med-2024-1138_ref_012","doi-asserted-by":"crossref","unstructured":"Zraik IM, He\u00df-Busch Y. Management of chemotherapy side effects and their long-term sequelae. Urologe A. 2021;60(7):862\u201371.","DOI":"10.1007\/s00120-021-01569-7"},{"key":"2025122201304107141_j_med-2024-1138_ref_013","doi-asserted-by":"crossref","unstructured":"Goa KL, Sorkin EM. Nitrendipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of hypertension. Drugs. 1987;33(2):123\u201355.","DOI":"10.2165\/00003495-198733020-00003"},{"key":"2025122201304107141_j_med-2024-1138_ref_014","doi-asserted-by":"crossref","unstructured":"Principe DR, Aissa AF, Kumar S, Pham T, Underwood PW, Nair R, et al. Calcium channel blockers potentiate gemcitabine chemotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2022;119(18):e2200143119.","DOI":"10.1073\/pnas.2200143119"},{"key":"2025122201304107141_j_med-2024-1138_ref_015","doi-asserted-by":"crossref","unstructured":"Wu L, Lin W, Liao Q, Wang H, Lin C, Tang L, et al. Calcium channel blocker nifedipine suppresses colorectal cancer progression and immune escape by preventing NFAT2 nuclear translocation. Cell Rep. 2020;33(4):108327.","DOI":"10.1016\/j.celrep.2020.108327"},{"key":"2025122201304107141_j_med-2024-1138_ref_016","doi-asserted-by":"crossref","unstructured":"Zhang Q, Zhou Y, Feng X, Gao Y, Huang C, Yao X. Low-dose orlistat promotes the therapeutic effect of oxaliplatin in colorectal cancer. Biomed Pharmacother. 2022;153:113426.","DOI":"10.1016\/j.biopha.2022.113426"},{"key":"2025122201304107141_j_med-2024-1138_ref_017","doi-asserted-by":"crossref","unstructured":"McKerr N, Mohd-Sarip A, Dorrian H, Breen C, A James J, McQuaid S, et al. CACNA1D overexpression and voltage-gated calcium channels in prostate cancer during androgen deprivation. Sci Rep. 2023;13(1):4683.","DOI":"10.1038\/s41598-023-28693-y"},{"key":"2025122201304107141_j_med-2024-1138_ref_018","doi-asserted-by":"crossref","unstructured":"Han H, Guo W, Shi W, Yu Y, Zhang Y, Ye X, et al. Hypertension and breast cancer risk: A systematic review and meta-analysis. Sci Rep. 2017;7:44877.","DOI":"10.1038\/srep44877"},{"key":"2025122201304107141_j_med-2024-1138_ref_019","doi-asserted-by":"crossref","unstructured":"Campi R, Rebez G, Klatte T, Roussel E, Ouizad I, Ingels A, et al. Effect of smoking, hypertension and lifestyle factors on kidney cancer - perspectives for prevention and screening programmes. Nat Rev Urol. 2023;20(11):669\u201381.","DOI":"10.1038\/s41585-023-00781-8"},{"key":"2025122201304107141_j_med-2024-1138_ref_020","doi-asserted-by":"crossref","unstructured":"Xuan K, Zhao T, Sun C, Patel AS, Liu H, Chen X, et al. The association between hypertension and colorectal cancer: A meta-analysis of observational studies. Eur J Cancer Prev. 2021;30(1):84\u201396.","DOI":"10.1097\/CEJ.0000000000000578"},{"key":"2025122201304107141_j_med-2024-1138_ref_021","doi-asserted-by":"crossref","unstructured":"Seo JH, Kim YD, Park CS, Han KD, Joo YH. Hypertension is associated with oral, laryngeal, and esophageal cancer: A nationwide population-based study. Sci Rep. 2020;10(1):10291.","DOI":"10.1038\/s41598-020-67329-3"},{"key":"2025122201304107141_j_med-2024-1138_ref_022","doi-asserted-by":"crossref","unstructured":"Santiago TM, Lopez LM. Nitrendipine: A new dihydropyridine calcium-channel antagonist for the treatment of hypertension. DICP. 1990;24(2):167\u201375.","DOI":"10.1177\/106002809002400211"},{"key":"2025122201304107141_j_med-2024-1138_ref_023","doi-asserted-by":"crossref","unstructured":"Nandi SK, Chatterjee N, Roychowdhury T, Pradhan A, Moiz S, Manna K, et al. Kaempferol with Verapamil impeded panoramic chemoevasion pathways in breast cancer through ROS overproduction and disruption of lysosomal biogenesis. Phytomedicine. 2023;113:154689.","DOI":"10.1016\/j.phymed.2023.154689"},{"key":"2025122201304107141_j_med-2024-1138_ref_024","doi-asserted-by":"crossref","unstructured":"Shiozaki A, Katsurahara K, Kudou M, Shimizu H, Kosuga T, Ito H, et al. Amlodipine and verapamil, voltage-gated Ca(2+) channel inhibitors, suppressed the growth of gastric cancer stem cells. Ann Surg Oncol. 2021;28(9):5400\u201311.","DOI":"10.1245\/s10434-021-09645-0"},{"key":"2025122201304107141_j_med-2024-1138_ref_025","doi-asserted-by":"crossref","unstructured":"Rybalchenko V, Prevarskaya N, Van Coppenolle F, Legrand G, Lemonnier L, Le Bourhis X, et al. Verapamil inhibits proliferation of LNCaP human prostate cancer cells influencing K+ channel gating. Mol Pharmacol. 2001;59(6):1376\u201387.","DOI":"10.1124\/mol.59.6.1376"},{"key":"2025122201304107141_j_med-2024-1138_ref_026","doi-asserted-by":"crossref","unstructured":"Liang SY, Xiao HK. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC. Open Med (Wars). 2023;18(1):20230801.","DOI":"10.1515\/med-2023-0801"},{"key":"2025122201304107141_j_med-2024-1138_ref_027","doi-asserted-by":"crossref","unstructured":"Li P, Zhong D, Gong PY. Synergistic effect of paclitaxel and verapamil to overcome multi-drug resistance in breast cancer cells. Biochem Biophys Res Commun. 2019;516(1):183\u20138.","DOI":"10.1016\/j.bbrc.2019.05.189"},{"key":"2025122201304107141_j_med-2024-1138_ref_028","doi-asserted-by":"crossref","unstructured":"Zheng W, Li M, Lin Y, Zhan X. Encapsulation of verapamil and doxorubicin by MPEG-PLA to reverse drug resistance in ovarian cancer. Biomed Pharmacother. 2018;108:565\u201373.","DOI":"10.1016\/j.biopha.2018.09.039"},{"key":"2025122201304107141_j_med-2024-1138_ref_029","doi-asserted-by":"crossref","unstructured":"Rogan AM, Hamilton TC, Young RC, Klecker Jr RW, Ozols RF. Reversal of adriamycin resistance by verapamil in human ovarian cancer. Science. 1984;224(4652):994\u20136.","DOI":"10.1126\/science.6372095"},{"key":"2025122201304107141_j_med-2024-1138_ref_030","doi-asserted-by":"crossref","unstructured":"Zhu J, Chen N, Zhou M, Guo J, Zhu C, Zhou J, et al. Calcium channel blockers versus other classes of drugs for hypertension. Cochrane Database Syst Rev. 2022;1(1):Cd003654.","DOI":"10.1002\/14651858.CD003654.pub6"},{"key":"2025122201304107141_j_med-2024-1138_ref_031","doi-asserted-by":"crossref","unstructured":"Cassidy J, Misset JL. Oxaliplatin-related side effects: characteristics and management. Semin Oncol. 2002;29(5 Suppl 15):11\u201320.","DOI":"10.1053\/sonc.2002.35524"},{"key":"2025122201304107141_j_med-2024-1138_ref_032","doi-asserted-by":"crossref","unstructured":"Prevarskaya N, Ouadid-Ahidouch H, Skryma R, Shuba Y. Remodelling of Ca2+ transport in cancer: how it contributes to cancer hallmarks? Philos Trans R Soc Lond B Biol Sci. 2014;369(1638):20130097.","DOI":"10.1098\/rstb.2013.0097"},{"key":"2025122201304107141_j_med-2024-1138_ref_033","doi-asserted-by":"crossref","unstructured":"Biasiotta A, D'Arcangelo D, Passarelli F, Nicodemi EM, Facchiano A. Ion channels expression and function are strongly modified in solid tumors and vascular malformations. J Transl Med. 2016;14(1):285.","DOI":"10.1186\/s12967-016-1038-y"},{"key":"2025122201304107141_j_med-2024-1138_ref_034","doi-asserted-by":"crossref","unstructured":"Lastraioli E, Iorio J, Arcangeli A. Ion channel expression as promising cancer biomarker. Biochim Biophys Acta. 2015;1848(10 Pt B):2685\u2013702.","DOI":"10.1016\/j.bbamem.2014.12.016"},{"key":"2025122201304107141_j_med-2024-1138_ref_035","doi-asserted-by":"crossref","unstructured":"Wang CY, Lai MD, Phan NN, Sun Z, Lin YC. Meta-analysis of public microarray datasets reveals voltage-gated calcium gene signatures in clinical cancer patients. PLoS One. 2015;10(7):e0125766.","DOI":"10.1371\/journal.pone.0125766"},{"key":"2025122201304107141_j_med-2024-1138_ref_036","doi-asserted-by":"crossref","unstructured":"O'reilly D, Downing T, Kouba S, Potier-Cartereau M, McKenna DJ, Vandier C, et al. CaV1.3 enhanced store operated calcium promotes resistance to androgen deprivation in prostate cancer. Cell Calcium. 2022;103:102554.","DOI":"10.1016\/j.ceca.2022.102554"},{"key":"2025122201304107141_j_med-2024-1138_ref_037","doi-asserted-by":"crossref","unstructured":"Ji Y, Han Z, Shao L, Zhao Y. Ultrasound-targeted microbubble destruction of calcium channel subunit \u03b1 1D siRNA inhibits breast cancer via G protein-coupled receptor 30. Oncol Rep. 2016;36(4):1886\u201392.","DOI":"10.3892\/or.2016.5031"},{"key":"2025122201304107141_j_med-2024-1138_ref_038","doi-asserted-by":"crossref","unstructured":"Xu W, Zheng J, Wang X, Zhou B, Chen H, Li G, et al. tRF-Val-CAC-016 modulates the transduction of CACNA1d-mediated MAPK signaling pathways to suppress the proliferation of gastric carcinoma. Cell Commun Signal. 2022;20(1):68.","DOI":"10.1186\/s12964-022-00857-9"}],"container-title":["Open Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/med-2024-1138\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/med-2024-1138\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T01:35:47Z","timestamp":1766367347000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/med-2024-1138\/html"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,1]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,10,8]]},"published-print":{"date-parts":[[2025,10,8]]}},"alternative-id":["10.1515\/med-2024-1138"],"URL":"https:\/\/doi.org\/10.1515\/med-2024-1138","relation":{},"ISSN":["2391-5463"],"issn-type":[{"value":"2391-5463","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,1]]},"article-number":"20241138"}}