Antitumor Activity of Simvastatin in Preclinical Models of Mantle Cell Lymphoma

SIMPLE SUMMARY: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma that remains incurable with standard therapy. A promising approach to overcome the low life expectancy of patients with MCL is drug repurposing, a strategy focused on finding novel therapeutic weapons in approved drugs. Statins are well-tolerated, inexpensive, and widely prescribed as cholesterol-lowering agents that have also shown anti-cancer activity. The present study aimed to elucidate the effect of simvastatin on MCL cells. Our preclinical data demonstrate for the first time that simvastatin treatment impairs MCL proliferation and triggers a caspase-independent, ROS-mediated death of MCL cultures. Furthermore, we show that simvastatin significantly inhibits MCL migration and invasion ability, thereby impairing the growth of MCL tumors, suggesting that the use of statins might be considered for repurpose as a precise MCL therapy. ABSTRACT: 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.