{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T21:11:40Z","timestamp":1790111500882,"version":"4.0.1"},"reference-count":39,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,15]],"date-time":"2022-11-15T00:00:00Z","timestamp":1668470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CD19\/00228"],"award-info":[{"award-number":["CD19\/00228"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PID2021-123039OB-C21"],"award-info":[{"award-number":["PID2021-123039OB-C21"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Spanish Ministry of Economy and Competitiveness","award":["CD19\/00228"],"award-info":[{"award-number":["CD19\/00228"]}]},{"name":"Spanish Ministry of Economy and Competitiveness","award":["PID2021-123039OB-C21"],"award-info":[{"award-number":["PID2021-123039OB-C21"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Mantle cell lymphoma (MCL) is a rare and aggressive subtype of B-cell non-Hodgkin lymphoma that remains incurable with standard therapy. Statins are well-tolerated, inexpensive, and widely prescribed as cholesterol-lowering agents to treat hyperlipidemia and to prevent cardiovascular diseases through the blockage of the mevalonate metabolic pathway. These drugs have also shown promising anti-cancer activity through pleiotropic effects including the induction of lymphoma cell death. However, their potential use as anti-MCL agents has not been evaluated so far. Aim: The present study aimed to investigate the activity of simvastatin on MCL cells. Methods: We evaluated the cytotoxicity of simvastatin in MCL cell lines by CellTiter-Glo and lactate dehydrogenase (LDH) release assays. Cell proliferation and mitotic index were assessed by direct cell recounting and histone H3-pSer10 immunostaining. Apoptosis induction and reactive oxygen species (ROS) generation were evaluated by flow cytometry. Cell migration and invasion properties were determined by transwell assay. The antitumoral effect of simvastatin in vivo was evaluated in a chick embryo chorioallantoic membrane (CAM) MCL xenograft model. Results: We show that treatment with simvastatin induced a 2 to 6-fold LDH release, inhibited more than 50% of cell proliferation, and enhanced the caspase-independent ROS-mediated death of MCL cells. The effective impairment of MCL cell survival was accompanied by the inhibition of AKT and mTOR phosphorylation. Moreover, simvastatin strongly decreased MCL cell migration and invasion ability, leading to a 55% tumor growth inhibition and a consistent diminution of bone marrow and spleen metastasis in vivo. Conclusion: Altogether, these data provide the first preclinical insight into the effect of simvastatin against MCL cells, suggesting that this agent might be considered for repurpose as a precise MCL therapy.<\/jats:p>","DOI":"10.3390\/cancers14225601","type":"journal-article","created":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T02:36:36Z","timestamp":1668566196000},"page":"5601","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Antitumor Activity of Simvastatin in Preclinical Models of Mantle Cell Lymphoma"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4148-9570","authenticated-orcid":false,"given":"Juliana Carvalho","family":"Santos","sequence":"first","affiliation":[{"name":"Lymphoma Translational Group, Josep Carreras Leukemia Research Institute, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8923-6025","authenticated-orcid":false,"given":"N\u00faria","family":"Profit\u00f3s-Pelej\u00e0","sequence":"additional","affiliation":[{"name":"Lymphoma Translational Group, Josep Carreras Leukemia Research Institute, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4529-7832","authenticated-orcid":false,"given":"Marcelo Lima","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Lymphoma Translational Group, Josep Carreras Leukemia Research Institute, 08916 Badalona, Spain"},{"name":"Laboratory of Immunopharmacology and Molecular Biology, Sao Francisco University Medical School, Braganca Paulista 01246-100, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0245-2257","authenticated-orcid":false,"given":"Ga\u00ebl","family":"Rou\u00e9","sequence":"additional","affiliation":[{"name":"Lymphoma Translational Group, Josep Carreras Leukemia Research Institute, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1182\/blood-2016-01-643569","article-title":"The 2016 revision of the World Health Organization classification of lymphoid neoplasms","volume":"127","author":"Swerdlow","year":"2016","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1182\/blood-2014-05-521898","article-title":"Mantle cell lymphoma: Evolving management strategies","volume":"125","author":"Campo","year":"2015","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S1535-6108(03)00028-X","article-title":"The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma","volume":"3","author":"Rosenwald","year":"2003","journal-title":"Cancer Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/0014-5793(76)80996-9","article-title":"Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme a reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity","volume":"72","author":"Endo","year":"1976","journal-title":"FEBS Lett."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.cell.2015.01.036","article-title":"A century of cholesterol and coronaries: From plaques to genes to statins","volume":"161","author":"Goldstein","year":"2015","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1182\/blood.V93.4.1308","article-title":"Increased sensitivity of acute myeloid leukemias to lovastatin-induced apoptosis: A potential therapeutic approach","volume":"93","author":"Dimitroulakos","year":"1999","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"682","DOI":"10.3324\/haematol.11020","article-title":"Simvastatin-dependent apoptosis in Hodgkin\u2019s lymphoma cells and growth impairment of human Hodgkin\u2019s tumors in vivo","volume":"92","author":"Sasse","year":"2007","journal-title":"Haematologica"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e518","DOI":"10.1038\/cddis.2013.44","article-title":"HMG-CoA reductase inhibitors induce apoptosis of lymphoma cells by promoting ROS generation and regulating Akt, Erk and p38 signals via suppression of mevalonate pathway","volume":"4","author":"Qi","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"43586","DOI":"10.1074\/jbc.M307194200","article-title":"p21-dependent Inhibition of Colon Cancer Cell Growth by Mevastatin Is Independent of Inhibition of G1 Cyclin-dependent Kinases","volume":"278","author":"Ukomadu","year":"2003","journal-title":"J. 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