Fluvastatin elicits apoptosis in primary and transformed mast cells (INC6P.305)

Abstract

Abstract Mast cell leukemia is a rare subtype of acute myelogenous leukemia. A majority of mast cell leukemias express the c-Kit mutation, D816V, which yields factor-independent growth. Understanding and treating mast cell hyperplasias and leukemias could be beneficial to both allergic 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. We report that Fluvastatin induces apoptosis in mouse bone marrow-derived mast cells (BMMC) in a dose-and time-dependent manner. Apoptosis was evidenced by DNA fragmentation and Caspase-3/7 activation. Interestingly, BMMC from the C57BL/6 background were responsive to Fluvastatin-mediated death, while those from 129/SvJ mice were completely resistant. Resistance was matched by a 2-fold induction of HMG CoA Reductase after Fluvastain treatment. Importantly, the mastocytoma line P815, which expresses mutant c-Kit, was readily killed by Fluvastatin, with an IC50 between 5-10µM, and maximum effects after 72 hours. Mitochondrial staining detected membrane disintegration after 48-72 hours, while cells tested positive for active Caspase-9 as early as 24-48 hours. These preliminary data support the theory that statin family drugs may be a new therapeutic approach for suppressing growth of both normal and transformed mast cells, and emphasize the contribution of genetic background to drug responsiveness.