Cytotoxicity-related lipidomic changes induced in double-hit Diffuse Large B-Cell Lymphoma after treatment with statins in vitro

Diffuse Large B-Cell Lymphoma (DLBCL) is the most common hematologic malignancy in the world and one of the deadliest. Since the introduction of anti-CD20 blocking antibodies prognosis has dramatically improved; however, over 40% of cases are resistant or recur after an initial remission. These outcomes largely depend on its underlying genomics, which makes it difficult to approach because it is also one of the most genetically diverse neoplasms. Therefore, research beyond its already extensively described molecular biology is necessary. Metabolic reprogramming at the lipid level is one of the least understood hallmarks of cancer, but its relevance is becoming increasingly evident because it accurately depicts cellular phenotype and because of the bioactive nature of many lipid species such as sphingosine and ceramide. Statins are widely prescribed drugs. Although they are classically used as cholesterol lowering medications, they are incredibly pleiotropic agents and are known to have antilymphomagenic properties. However, the underlying mechanisms leading to these effects are still unclear. In this work, it was hypothesized that statins induce a metabolic shift that promotes the accumulation of cytotoxic lipids, triggering cell death. To approach this, an aggressive lymphoma cell line was treated with different combinations of statin-containing therapeutic regimens. Cell cycle was assessed with flow cytometry, and several lipid species were quantified through mass spectrometry. Our data suggests that atorvastatin synergizes with R-CHOP to produce G1/S cell cycle arrest, and that this effect might be partially driven by sphingosine. This is the first work to evaluate the sphingolipidomic effect of statins in the cancer context and gives rise to clinical research that could lead to novel biomarkers and drug repurposing.