RT Journal Article
SR Electronic
T1 Fluvastatin Induces Apoptosis in Primary and Transformed Mast Cells
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 104
OP 112
DO 10.1124/jpet.119.264234
VO 374
IS 1
A1 Patrick A. Paez
A1 Motunrayo Kolawole
A1 Marcela T. Taruselli
A1 Siddarth Ajith
A1 Jordan M. Dailey
A1 Sydney A. Kee
A1 Tamara T. Haque
A1 Brian O. Barnstein
A1 Jamie Josephine Avila McLeod
A1 Heather L. Caslin
A1 Kasalina N. Kiwanuka
A1 Yoshihiro Fukuoka
A1 Quang T. Le
A1 Lawrence B. Schwartz
A1 David B. Straus
A1 David A. Gewirtz
A1 Rebecca K. Martin
A1 John J. Ryan
YR 2020
UL http://jpet.aspetjournals.org/content/374/1/104.abstract
AB Statin drugs are widely employed in the clinic to reduce serum cholesterol. Because of their hydroxymethylglutaryl coenzyme A reductase 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 immunoglobulin E (IgE)-mediated mast cell activation, suggesting these drugs might be useful in treating allergic disease. Although 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 and 3.5 μM in both cell types, concentrations similar to the reported fluvastatin serum Cmax value. Apoptosis was correlated with reduced stem cell factor (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 stem cell factor (SCF)-induced survival signals. This drug may be an effective means of suppressing mast cell survival.