TY - JOUR T1 - Fluvastatin Induces Apoptosis in Primary and Transformed Mast Cells JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.119.264234 SP - jpet.119.264234 AU - Patrick A Paez AU - E. Motunrayo Kolawole AU - Marcela T Taruselli AU - Siddarth Ajith AU - Jordan M Dailey AU - Sydney A Kee AU - Tamara T Haque AU - Brian O Barnstein AU - Jamie Josephine Avila McLeod AU - Heather L Caslin AU - Kasalina N Kiwanuka AU - Yoshihiro Fukuoka AU - Quang T. Le AU - Lawrence B. Schwartz AU - David B Straus AU - David A Gewirtz AU - Rebecca K Martin AU - John J Ryan Y1 - 2020/01/01 UR - http://jpet.aspetjournals.org/content/early/2020/05/20/jpet.119.264234.abstract N2 - Statin drugs are widely employed in the clinic to reduce serum cholesterol. Due to their HMG CoA reductase (HMGCR) antagonism, statins also reduce isoprenyl lipids necessary for the membrane anchorage and signaling of small G-proteins in the Ras superfamily. We previously found that statins suppress IgE-mediated mast cell activation, suggesting these drugs might be useful in treating allergic disease. While IgE-induced function is critical to allergic inflammation, mast cell proliferation and survival also impact atopic disease and mast cell neoplasia. In this study, we describe fluvastatin-mediated apoptosis in primary and transformed mast cells. An IC50 was achieved between 0.8-3.5μM in both cell types, concentrations similar to the reported fluvastatin serum Cmax value. Apoptosis was correlated with reduced SCF-mediated signal transduction, mitochondrial dysfunction, and caspase activation. Complementing these data, we found that p53 deficiency or Bcl-2 overexpression reduced fluvastatin-induced apoptosis. We also noted evidence of cytoprotective autophagy in primary mast cells treated with fluvastatin. Finally, we found that intraperitoneal fluvastatin treatment reduced peritoneal mast cell numbers in vivo. These findings offer insight into the mechanisms of mast cell survival and support the possible utility of statins in mast cell-associated allergic and neoplastic diseases.SIGNIFICANCE STATEMENT Fluvastatin, a statin drug used to lower cholesterol, induces apoptosis in primary and transformed mast cells by antagonizing protein isoprenylation, effectively inhibiting SCF-induced survival signals. This drug may be an effective means of suppressing mast cell survival. ER -