Antitumor Activity of Simvastatin in Preclinical Models of Mantle Cell Lymphoma
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 dis...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/22/5601 |
| _version_ | 1797465705273098240 |
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| author | Juliana Carvalho Santos Núria Profitós-Pelejà Marcelo Lima Ribeiro Gaël Roué |
| author_facet | Juliana Carvalho Santos Núria Profitós-Pelejà Marcelo Lima Ribeiro Gaël Roué |
| author_sort | Juliana Carvalho Santos |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T18:26:16Z |
| format | Article |
| id | doaj.art-501f141fc9d3488f8526ef5eb40125b1 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T18:26:16Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-501f141fc9d3488f8526ef5eb40125b12023-11-24T07:53:48ZengMDPI AGCancers2072-66942022-11-011422560110.3390/cancers14225601Antitumor Activity of Simvastatin in Preclinical Models of Mantle Cell LymphomaJuliana Carvalho Santos0Núria Profitós-Pelejà1Marcelo Lima Ribeiro2Gaël Roué3Lymphoma Translational Group, Josep Carreras Leukemia Research Institute, 08916 Badalona, SpainLymphoma Translational Group, Josep Carreras Leukemia Research Institute, 08916 Badalona, SpainLymphoma Translational Group, Josep Carreras Leukemia Research Institute, 08916 Badalona, SpainLymphoma Translational Group, Josep Carreras Leukemia Research Institute, 08916 Badalona, SpainBackground: 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.https://www.mdpi.com/2072-6694/14/22/5601statinsmantle cell lymphomacell proliferationcell death |
| spellingShingle | Juliana Carvalho Santos Núria Profitós-Pelejà Marcelo Lima Ribeiro Gaël Roué Antitumor Activity of Simvastatin in Preclinical Models of Mantle Cell Lymphoma Cancers statins mantle cell lymphoma cell proliferation cell death |
| title | Antitumor Activity of Simvastatin in Preclinical Models of Mantle Cell Lymphoma |
| title_full | Antitumor Activity of Simvastatin in Preclinical Models of Mantle Cell Lymphoma |
| title_fullStr | Antitumor Activity of Simvastatin in Preclinical Models of Mantle Cell Lymphoma |
| title_full_unstemmed | Antitumor Activity of Simvastatin in Preclinical Models of Mantle Cell Lymphoma |
| title_short | Antitumor Activity of Simvastatin in Preclinical Models of Mantle Cell Lymphoma |
| title_sort | antitumor activity of simvastatin in preclinical models of mantle cell lymphoma |
| topic | statins mantle cell lymphoma cell proliferation cell death |
| url | https://www.mdpi.com/2072-6694/14/22/5601 |
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