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Research ArticleInflammation, Immunopharmacology, and Asthma

Fluvastatin Induces Apoptosis in Primary and Transformed Mast Cells

Patrick A. Paez, Motunrayo Kolawole, Marcela T. Taruselli, Siddarth Ajith, Jordan M. Dailey, Sydney A. Kee, Tamara T. Haque, Brian O. Barnstein, Jamie Josephine Avila McLeod, Heather L. Caslin, Kasalina N. Kiwanuka, Yoshihiro Fukuoka, Quang T. Le, Lawrence B. Schwartz, David B. Straus, David A. Gewirtz, Rebecca K. Martin and John J. Ryan
Journal of Pharmacology and Experimental Therapeutics July 2020, 374 (1) 104-112; DOI: https://doi.org/10.1124/jpet.119.264234
Patrick A. Paez
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
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Motunrayo Kolawole
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
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Marcela T. Taruselli
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
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Siddarth Ajith
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
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Jordan M. Dailey
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
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Sydney A. Kee
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
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Tamara T. Haque
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
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Brian O. Barnstein
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
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Jamie Josephine Avila McLeod
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
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Heather L. Caslin
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
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Kasalina N. Kiwanuka
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
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Yoshihiro Fukuoka
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
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Quang T. Le
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
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Lawrence B. Schwartz
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
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David B. Straus
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
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David A. Gewirtz
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Rebecca K. Martin
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
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John J. Ryan
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
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Abstract

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.

Footnotes

    • Received November 25, 2019.
    • Accepted April 1, 2020.
  • This work was supported by grants from the National Institutes of Health [R01AI138495 and R21AI138494 (to J.J.R)].

  • https://doi.org/10.1124/jpet.119.264234.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 374 (1)
Journal of Pharmacology and Experimental Therapeutics
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1 Jul 2020
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Research ArticleInflammation, Immunopharmacology, and Asthma

Fluvastatin Induces Mast Cell Apoptosis

Patrick A. Paez, Motunrayo Kolawole, Marcela T. Taruselli, Siddarth Ajith, Jordan M. Dailey, Sydney A. Kee, Tamara T. Haque, Brian O. Barnstein, Jamie Josephine Avila McLeod, Heather L. Caslin, Kasalina N. Kiwanuka, Yoshihiro Fukuoka, Quang T. Le, Lawrence B. Schwartz, David B. Straus, David A. Gewirtz, Rebecca K. Martin and John J. Ryan
Journal of Pharmacology and Experimental Therapeutics July 1, 2020, 374 (1) 104-112; DOI: https://doi.org/10.1124/jpet.119.264234

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Research ArticleInflammation, Immunopharmacology, and Asthma

Fluvastatin Induces Mast Cell Apoptosis

Patrick A. Paez, Motunrayo Kolawole, Marcela T. Taruselli, Siddarth Ajith, Jordan M. Dailey, Sydney A. Kee, Tamara T. Haque, Brian O. Barnstein, Jamie Josephine Avila McLeod, Heather L. Caslin, Kasalina N. Kiwanuka, Yoshihiro Fukuoka, Quang T. Le, Lawrence B. Schwartz, David B. Straus, David A. Gewirtz, Rebecca K. Martin and John J. Ryan
Journal of Pharmacology and Experimental Therapeutics July 1, 2020, 374 (1) 104-112; DOI: https://doi.org/10.1124/jpet.119.264234
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