{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T06:17:22Z","timestamp":1764656242260,"version":"build-2065373602"},"reference-count":41,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T00:00:00Z","timestamp":1681171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FEDER (Fundo Europeu de Desenvolvimento Regional) through the COMPETE 2020 Operational Programme for Competitiveness and Internationalization (POCI), Portugal 2020","award":["\u201cRISE\u2013LA\/P\/0053\/2020","IF\/00092\/2014\/CP1255\/CT0004"],"award-info":[{"award-number":["\u201cRISE\u2013LA\/P\/0053\/2020","IF\/00092\/2014\/CP1255\/CT0004"]}]},{"name":"Portuguese funds through FCT (Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia) in a framework of the projects in CINTESIS, R&amp;D Unit (reference UIDB\/4255\/2020)","award":["\u201cRISE\u2013LA\/P\/0053\/2020","IF\/00092\/2014\/CP1255\/CT0004"],"award-info":[{"award-number":["\u201cRISE\u2013LA\/P\/0053\/2020","IF\/00092\/2014\/CP1255\/CT0004"]}]},{"name":"FCT and FEDER (European Union)","award":["\u201cRISE\u2013LA\/P\/0053\/2020","IF\/00092\/2014\/CP1255\/CT0004"],"award-info":[{"award-number":["\u201cRISE\u2013LA\/P\/0053\/2020","IF\/00092\/2014\/CP1255\/CT0004"]}]},{"name":"CHAIR in Onco-Innovation at FMUP","award":["\u201cRISE\u2013LA\/P\/0053\/2020","IF\/00092\/2014\/CP1255\/CT0004"],"award-info":[{"award-number":["\u201cRISE\u2013LA\/P\/0053\/2020","IF\/00092\/2014\/CP1255\/CT0004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Cancer is a set of complex diseases, being one of the leading causes of death worldwide. Despite a lot of research on the molecular pathways and effective treatments, there are still huge gaps. Indeed, the development of new anti-cancer drugs is a complex process. To face this problem, drug repurposing is being increasingly applied. This approach aims to identify new indications for already approved drugs. In this regard, statins (clinically used for reducing cholesterol levels) are reported to induce anti-cancer effects, particularly by inducing apoptosis and altering the tumor microenvironment. Atorvastatin is a type of statin with several potentialities as an anti-cancer agent, supported by several studies. Our study aimed to explore the effect of this drug in SH-SY5Y human neuroblastoma cells. Additionally, we also aimed to understand how this drug acts under hypoxia and the inhibition of hypoxia-inducible factor-1 (HIF-1). For that purpose, we assessed cellular viability\/morphology after exposure to different concentrations of atorvastatin, with or without chemically induced hypoxia with chloride cobalt (CoCl2) and with or without echinomycin (HIF-1\u03b1 inhibitor). Our results supported the cytotoxic effects of atorvastatin. Additionally, we also revealed that besides these effects, under hypoxia, this drug induced proliferation of the neuroblastoma cells, supporting the importance of different stimuli and environment on the effect of drugs on cancer cells.<\/jats:p>","DOI":"10.3390\/cimb45040218","type":"journal-article","created":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T02:02:33Z","timestamp":1681178553000},"page":"3333-3346","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Involvement of Hypoxia in the Response of Neuroblastoma Cells to the Exposure of Atorvastatin"],"prefix":"10.3390","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8231-1560","authenticated-orcid":false,"given":"Ana Salom\u00e9","family":"Correia","sequence":"first","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7003-4957","authenticated-orcid":false,"given":"Lara","family":"Marques","sequence":"additional","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1283-1042","authenticated-orcid":false,"given":"Nuno","family":"Vale","sequence":"additional","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"Department of Community Medicine, Information and Health Decision Sciences (MEDCIDS), Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,11]]},"reference":[{"key":"ref_1","unstructured":"(2023, February 20). Cancer. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/cancer."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Correia, A., Silva, D., Correia, A., Vilanova, M., G\u00e4rtner, F., and Vale, N. (2018). Study of New Therapeutic Strategies to Combat Breast Cancer Using Drug Combinations. Biomolecules, 8.","DOI":"10.3390\/biom8040175"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/s41392-020-00213-8","article-title":"Overcoming cancer therapeutic bottleneck by drug repurposing","volume":"5","author":"Zhang","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1186\/s12967-016-1031-5","article-title":"Repurposing of approved cardiovascular drugs","volume":"14","author":"Ishida","year":"2016","journal-title":"J. Transl. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Duarte, D., and Vale, N. (2020). New Trends for Antimalarial Drugs: Synergism between Antineoplastics and Antimalarials on Breast Cancer Cells. Biomolecules, 10.","DOI":"10.3390\/biom10121623"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"204","DOI":"10.3892\/ol.2022.13325","article-title":"Metformin: A promising drug for human cancers (Review)","volume":"24","author":"Wu","year":"2022","journal-title":"Oncol. Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"113","DOI":"10.2174\/1574892814666190514104035","article-title":"Repurposing Disulfiram as An Anti-Cancer Agent: Updated Review on Literature and Patents","volume":"14","author":"Ekinci","year":"2019","journal-title":"Recent Pat. Anti-Cancer Drug Discov."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/2162-3619-1-27","article-title":"Thalidomide and its analogues in the treatment of Multiple Myeloma","volume":"1","author":"Latif","year":"2012","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1186\/s13046-021-02041-2","article-title":"Statins: A repurposed drug to fight cancer","volume":"40","author":"Jiang","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"573","DOI":"10.5306\/wjco.v11.i8.573","article-title":"Statins in risk-reduction and treatment of cancer","volume":"11","author":"Barbalata","year":"2020","journal-title":"World J. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1023\/A:1020355621043","article-title":"Lovastatin alters cytoskeleton organization and inhibits experimental metastasis of mammary carcinoma cells","volume":"19","author":"Farina","year":"2002","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"83","DOI":"10.2147\/HP.S93413","article-title":"The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy","volume":"3","author":"Muz","year":"2015","journal-title":"Hypoxia"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"d\u2019Hose, D., Mignion, L., Hamelin, L., Sonveaux, P., Jordan, B.F., and Gallez, B. (2022). Statins Alleviate Tumor Hypoxia in Prostate Cancer Models by Decreasing Oxygen Consumption: An Opportunity for Radiosensitization?. Biomolecules, 12.","DOI":"10.3390\/biom12101418"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1038\/s41416-021-01529-0","article-title":"Atorvastatin facilitates chemotherapy effects in metastatic triple-negative breast cancer","volume":"125","author":"Marti","year":"2021","journal-title":"Br. J. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"350","DOI":"10.4111\/icu.20210411","article-title":"Atorvastatin regulates the migration and invasion of prostate cancer through the epithelial-mesenchymal transformation and matrix metalloproteinase pathways","volume":"63","author":"Zhu","year":"2022","journal-title":"Investig. Clin. Urol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1007\/s12032-022-01880-z","article-title":"Atorvastatin induces downregulation of matrix metalloproteinase-2\/9 in MDA-MB-231 triple negative breast cancer cells","volume":"40","author":"Ozkan","year":"2022","journal-title":"Med. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s12672-022-00598-8","article-title":"Atorvastatin improves cisplatin sensitivity through modulation of cholesteryl ester homeostasis in breast cancer cells","volume":"13","author":"Cochran","year":"2022","journal-title":"Discov. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Choe, E.-J., Lee, C.-H., Bae, J.-H., Park, J.-M., Park, S.-S., and Baek, M.-C. (2022). Atorvastatin Enhances the Efficacy of Immune Checkpoint Therapy and Suppresses the Cellular and Extracellular Vesicle PD-L1. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14081660"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.yapd.2011.03.011","article-title":"Neuroblastoma","volume":"58","author":"Colon","year":"2011","journal-title":"Adv. Pediatr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/978-1-62703-640-5_2","article-title":"Considerations for the Use of SH-SY5Y Neuroblastoma Cells in Neurobiology","volume":"Volume 1078","author":"Kovalevich","year":"2013","journal-title":"Methods in Molecular Biology (Clifton, N.J.)"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1002\/jat.3749","article-title":"The use of cobalt chloride as a chemical hypoxia model","volume":"39","year":"2019","journal-title":"J. Appl. Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1089\/jir.2005.25.297","article-title":"Review: Hypoxia-inducible factor-1 (HIF-1): A novel transcription factor in immune reactions","volume":"25","author":"Stiehl","year":"2005","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/emm.2004.1","article-title":"Hypoxia-inducible factor (HIF-1)alpha: Its protein stability and biological functions","volume":"36","author":"Lee","year":"2004","journal-title":"Exp. Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3671","DOI":"10.1007\/s00204-020-02936-7","article-title":"Inhibition and induction of CYP enzymes in humans: An update","volume":"94","author":"Hakkola","year":"2020","journal-title":"Arch. Toxicol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1080\/00498250802334391","article-title":"Contribution of cytochrome P450 3A4 and 3A5 to the metabolism of atorvastatin","volume":"38","author":"Park","year":"2008","journal-title":"Xenobiotica"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1038\/nprot.2008.75","article-title":"Neutral red uptake assay for the estimation of cell viability\/cytotoxicity","volume":"3","author":"Repetto","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ghasemi, M., Turnbull, T., Sebastian, S., and Kempson, I. (2021). The MTT Assay: Utility, Limitations, Pitfalls, and Interpretation in Bulk and Single-Cell Analysis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222312827"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Correia, A.S., Fraga, S., Teixeira, J.P., and Vale, N. (2022). Cell Model of Depression: Reduction of Cell Stress with Mirtazapine. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094942"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/S0008-6363(99)00384-3","article-title":"Morphologic and biochemical hallmarks of apoptosis","volume":"45","author":"Saraste","year":"2000","journal-title":"Cardiovasc. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"692","DOI":"10.21037\/tlcr.2019.09.08","article-title":"Current perspectives on statins as potential anti-cancer therapeutics: Clinical outcomes and underlying molecular mechanisms","volume":"8","year":"2019","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1007\/s12035-010-8122-8","article-title":"Simvastatin Stimulates Production of the Antiapoptotic Protein Bcl-2 via Endothelin-1 and NFATc3 in SH-SY5Y Cells","volume":"41","author":"Butterick","year":"2010","journal-title":"Mol. Neurobiol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Atil, B., Sieczkowski, E., and Hohenegger, M. (2012). Statins reduce endogenous dolichol levels in the neuroblastoma cell line SH-SY5Y. BMC Pharmacol. Toxicol., 13.","DOI":"10.1186\/2050-6511-13-S1-A51"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1609802","DOI":"10.3389\/pore.2021.1609802","article-title":"Hypoxia Signaling in Cancer: From Basics to Clinical Practice","volume":"27","author":"Kopper","year":"2021","journal-title":"Pathol. Oncol. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1016\/j.ymthe.2018.06.005","article-title":"Atorvastatin Inhibits the HIF1\u03b1-PPAR Axis, Which Is Essential for Maintaining the Function of Human Induced Pluripotent Stem Cells","volume":"26","author":"Nakashima","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_35","first-page":"2053","article-title":"Atorvastatin combined with routine therapy on HIF-1, VEGF concentration and cardiac function in rats with acute myocardial infarction","volume":"19","author":"Yu","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_36","unstructured":"(2023, March 02). Atorvastatin | C33H35FN2O5. PubChem, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Atorvastatin."},{"key":"ref_37","unstructured":"(2023, March 02). AID 781329\u2014pKa (Acid-Base Dissociation Constant) as Determined by Other Workers. PubChem, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/bioassay\/781329#sid=103554720."},{"key":"ref_38","unstructured":"(2023, March 02). Atorvastatin: Uses, Interactions, Mechanism of Action. DrugBank Online, Available online: https:\/\/go.drugbank.com\/drugs\/DB01076."},{"key":"ref_39","first-page":"263","article-title":"Basic Review of the Cytochrome P450 System","volume":"4","author":"McDonnell","year":"2013","journal-title":"J. Adv. Pract. Oncol."},{"key":"ref_40","unstructured":"Valentovic, M. (2007). xPharm: The Comprehensive Pharmacology Reference, Elsevier."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1080\/17425255.2020.1801634","article-title":"An updated review of pharmacokinetic drug interactions and pharmacogenetics of statins","volume":"16","author":"Hirota","year":"2020","journal-title":"Expert Opin. Drug Metab. Toxicol."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/45\/4\/218\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:13:34Z","timestamp":1760123614000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/45\/4\/218"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,11]]},"references-count":41,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["cimb45040218"],"URL":"https:\/\/doi.org\/10.3390\/cimb45040218","relation":{},"ISSN":["1467-3045"],"issn-type":[{"type":"electronic","value":"1467-3045"}],"subject":[],"published":{"date-parts":[[2023,4,11]]}}}