Fluvastatin Induces Apoptosis in Primary and Transformed Mast Cells.

Autor: Paez PA; Departments of Biology (P.A.P., E.M.K., M.T.T., S.A., J.M.D., S.A.K., T.T.H., B.O.B., J.J.A.M., H.L.C., K.N.K., Y.F., D. B.S., J.J.R.), Internal Medicine (Q.T.L., L.B.S.), Pharmacology and Toxicology (D.A.G.), and Microbiology and Immunology (R.K.M.), Virginia Commonwealth University, Richmond, Virginia., Kolawole M; Departments of Biology (P.A.P., E.M.K., M.T.T., S.A., J.M.D., S.A.K., T.T.H., B.O.B., J.J.A.M., H.L.C., K.N.K., Y.F., D. B.S., J.J.R.), Internal Medicine (Q.T.L., L.B.S.), Pharmacology and Toxicology (D.A.G.), and Microbiology and Immunology (R.K.M.), Virginia Commonwealth University, Richmond, Virginia., Taruselli MT; Departments of Biology (P.A.P., E.M.K., M.T.T., S.A., J.M.D., S.A.K., T.T.H., B.O.B., J.J.A.M., H.L.C., K.N.K., Y.F., D. B.S., J.J.R.), Internal Medicine (Q.T.L., L.B.S.), Pharmacology and Toxicology (D.A.G.), and Microbiology and Immunology (R.K.M.), Virginia Commonwealth University, Richmond, Virginia., Ajith S; Departments of Biology (P.A.P., E.M.K., M.T.T., S.A., J.M.D., S.A.K., T.T.H., B.O.B., J.J.A.M., H.L.C., K.N.K., Y.F., D. B.S., J.J.R.), Internal Medicine (Q.T.L., L.B.S.), Pharmacology and Toxicology (D.A.G.), and Microbiology and Immunology (R.K.M.), Virginia Commonwealth University, Richmond, Virginia., Dailey JM; Departments of Biology (P.A.P., E.M.K., M.T.T., S.A., J.M.D., S.A.K., T.T.H., B.O.B., J.J.A.M., H.L.C., K.N.K., Y.F., D. B.S., J.J.R.), Internal Medicine (Q.T.L., L.B.S.), Pharmacology and Toxicology (D.A.G.), and Microbiology and Immunology (R.K.M.), Virginia Commonwealth University, Richmond, Virginia., Kee SA; Departments of Biology (P.A.P., E.M.K., M.T.T., S.A., J.M.D., S.A.K., T.T.H., B.O.B., J.J.A.M., H.L.C., K.N.K., Y.F., D. B.S., J.J.R.), Internal Medicine (Q.T.L., L.B.S.), Pharmacology and Toxicology (D.A.G.), and Microbiology and Immunology (R.K.M.), Virginia Commonwealth University, Richmond, Virginia., Haque TT; Departments of Biology (P.A.P., E.M.K., M.T.T., S.A., J.M.D., S.A.K., T.T.H., B.O.B., J.J.A.M., H.L.C., K.N.K., Y.F., D. B.S., J.J.R.), Internal Medicine (Q.T.L., L.B.S.), Pharmacology and Toxicology (D.A.G.), and Microbiology and Immunology (R.K.M.), Virginia Commonwealth University, Richmond, Virginia., Barnstein BO; Departments of Biology (P.A.P., E.M.K., M.T.T., S.A., J.M.D., S.A.K., T.T.H., B.O.B., J.J.A.M., H.L.C., K.N.K., Y.F., D. B.S., J.J.R.), Internal Medicine (Q.T.L., L.B.S.), Pharmacology and Toxicology (D.A.G.), and Microbiology and Immunology (R.K.M.), Virginia Commonwealth University, Richmond, Virginia., McLeod JJA; Departments of Biology (P.A.P., E.M.K., M.T.T., S.A., J.M.D., S.A.K., T.T.H., B.O.B., J.J.A.M., H.L.C., K.N.K., Y.F., D. B.S., J.J.R.), Internal Medicine (Q.T.L., L.B.S.), Pharmacology and Toxicology (D.A.G.), and Microbiology and Immunology (R.K.M.), Virginia Commonwealth University, Richmond, Virginia., Caslin HL; Departments of Biology (P.A.P., E.M.K., M.T.T., S.A., J.M.D., S.A.K., T.T.H., B.O.B., J.J.A.M., H.L.C., K.N.K., Y.F., D. B.S., J.J.R.), Internal Medicine (Q.T.L., L.B.S.), Pharmacology and Toxicology (D.A.G.), and Microbiology and Immunology (R.K.M.), Virginia Commonwealth University, Richmond, Virginia., Kiwanuka KN; Departments of Biology (P.A.P., E.M.K., M.T.T., S.A., J.M.D., S.A.K., T.T.H., B.O.B., J.J.A.M., H.L.C., K.N.K., Y.F., D. B.S., J.J.R.), Internal Medicine (Q.T.L., L.B.S.), Pharmacology and Toxicology (D.A.G.), and Microbiology and Immunology (R.K.M.), Virginia Commonwealth University, Richmond, Virginia., Fukuoka Y; Departments of Biology (P.A.P., E.M.K., M.T.T., S.A., J.M.D., S.A.K., T.T.H., B.O.B., J.J.A.M., H.L.C., K.N.K., Y.F., D. B.S., J.J.R.), Internal Medicine (Q.T.L., L.B.S.), Pharmacology and Toxicology (D.A.G.), and Microbiology and Immunology (R.K.M.), Virginia Commonwealth University, Richmond, Virginia., Le QT; Departments of Biology (P.A.P., E.M.K., M.T.T., S.A., J.M.D., S.A.K., T.T.H., B.O.B., J.J.A.M., H.L.C., K.N.K., Y.F., D. B.S., J.J.R.), Internal Medicine (Q.T.L., L.B.S.), Pharmacology and Toxicology (D.A.G.), and Microbiology and Immunology (R.K.M.), Virginia Commonwealth University, Richmond, Virginia., Schwartz LB; Departments of Biology (P.A.P., E.M.K., M.T.T., S.A., J.M.D., S.A.K., T.T.H., B.O.B., J.J.A.M., H.L.C., K.N.K., Y.F., D. B.S., J.J.R.), Internal Medicine (Q.T.L., L.B.S.), Pharmacology and Toxicology (D.A.G.), and Microbiology and Immunology (R.K.M.), Virginia Commonwealth University, Richmond, Virginia., Straus DB; Departments of Biology (P.A.P., E.M.K., M.T.T., S.A., J.M.D., S.A.K., T.T.H., B.O.B., J.J.A.M., H.L.C., K.N.K., Y.F., D. B.S., J.J.R.), Internal Medicine (Q.T.L., L.B.S.), Pharmacology and Toxicology (D.A.G.), and Microbiology and Immunology (R.K.M.), Virginia Commonwealth University, Richmond, Virginia., Gewirtz DA; Departments of Biology (P.A.P., E.M.K., M.T.T., S.A., J.M.D., S.A.K., T.T.H., B.O.B., J.J.A.M., H.L.C., K.N.K., Y.F., D. B.S., J.J.R.), Internal Medicine (Q.T.L., L.B.S.), Pharmacology and Toxicology (D.A.G.), and Microbiology and Immunology (R.K.M.), Virginia Commonwealth University, Richmond, Virginia., Martin RK; Departments of Biology (P.A.P., E.M.K., M.T.T., S.A., J.M.D., S.A.K., T.T.H., B.O.B., J.J.A.M., H.L.C., K.N.K., Y.F., D. B.S., J.J.R.), Internal Medicine (Q.T.L., L.B.S.), Pharmacology and Toxicology (D.A.G.), and Microbiology and Immunology (R.K.M.), Virginia Commonwealth University, Richmond, Virginia., Ryan JJ; Departments of Biology (P.A.P., E.M.K., M.T.T., S.A., J.M.D., S.A.K., T.T.H., B.O.B., J.J.A.M., H.L.C., K.N.K., Y.F., D. B.S., J.J.R.), Internal Medicine (Q.T.L., L.B.S.), Pharmacology and Toxicology (D.A.G.), and Microbiology and Immunology (R.K.M.), Virginia Commonwealth University, Richmond, Virginia jjryan@vcu.edu.
Jazyk: angličtina
Zdroj: The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2020 Jul; Vol. 374 (1), pp. 104-112. Date of Electronic Publication: 2020 May 20.
DOI: 10.1124/jpet.119.264234
Abstrakt: 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 IC 50 was achieved between 0.8 and 3.5 μM in both cell types, concentrations similar to the reported fluvastatin serum C max 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.
(Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze: MEDLINE
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