Fluvastatin induces mast cell apoptosis and autophagy: effects on primary and transformed mast cells

Mast cells are best known for their role in inflammatory and allergic disease. Mast cell leukemia is a rare subtype of acute myelogenous leukemia, most of which express the c-Kit mutation, D816V, that yields factor-independent growth. Understanding and treating mast cell hyperplasia and leukemia could be beneficial to both inflammatory and malignant diseases. Recently the family of statin drugs, widely employed as HMG CoA Reductase inhibitors to lower serum cholesterol, have also been found to be immunosuppressive. However, statin effects on mast cell survival are not known. We report that Fluvastatin induces apoptosis in mouse bone marrow-derived mast cells (BMMC) and P815 mastocytoma cells in a dose- and time-dependent manner. Apoptosis was evidenced by DNA fragmentation and caspase activation. Importantly, the mastocytoma line P815, which expresses mutant c-Kit, was readily killed by Fluvastatin, with an IC50 of 5–10μM and apoptosis peaking at 72 hours. An up-regulation of the mutated c-Kit receptor was seen at 12 hours, followed by mitochondrial membrane instability and Caspase-9 activation within 24–28 hours. Finally, preliminary evidence of autophagy was detected during fluvastatin treatment. Interestingly, autophagy appeared to be cytoprotective in primary mast cells but cytotoxic in P815 mastocytoma cells. These preliminary data support the theory that statin family drugs induce mast cell autophagy and apoptosis, lending new therapeutic approaches for suppressing growth of both normal and transformed mast cells.