Pitavastatin Is Anti-Leukemic in a Bone Marrow Microenvironment Model of B-Lineage Acute Lymphoblastic Leukemia.

Abstract

Simple SummaryChemoresistance after chemotherapy is a negative prognostic indicator for B-cell acute lymphoblastic leukemia (ALL), necessitating the search for novel therapies. By growing ALL cells together with bone marrow stromal cells, we developed a chemoresistant ALL model. Using this model, we found that the lipid lowering drug pitavastatin had antileukemic activity in this chemoresistant co-culture model. Our data suggests that pitavastatin may be a novel treatment option for repurposing in chemoresistant, relapse ALL.The lack of complete therapeutic success in the treatment of B-cell acute lymphoblastic leukemia (ALL) has been attributed, in part, to a subset of cells within the bone marrow microenvironment that are drug resistant. Recently, the cholesterol synthesis inhibitor, pitavastatin (PIT), was shown to be active in acute myeloid leukemia, prompting us to evaluate it in our in vitro co-culture model, which supports a chemo-resistant ALL population. We used phospho-protein profiling to evaluate the use of lipid metabolic active compounds in these chemo-resistant cells, due to the up-regulation of multiple active survival signals. In a co-culture with stromal cells, a shift towards anabolic processes occurred, which was further confirmed by assays showing increased lipid content. The treatment of REH leukemia cells with pitavastatin in the co-culture model resulted in significantly higher leukemic cell death than exposure to the standard-of-care chemotherapeutic agent, cytarabine (Ara-C). Our data demonstrates the use of pitavastatin as a possible alternative treatment strategy to improve patient outcomes in chemo-resistant, relapsed ALL.