PMID- 32434944
OWN - NLM
STAT- MEDLINE
DCOM- 20201112
LR  - 20210702
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 374
IP  - 1
DP  - 2020 Jul
TI  - Fluvastatin Induces Apoptosis in Primary and Transformed Mast Cells.
PG  - 104-112
LID - 10.1124/jpet.119.264234 [doi]
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 IC(50) 
      was achieved between 0.8 and 3.5 muM 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.
CI  - Copyright (c) 2020 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Paez, Patrick A
AU  - Paez PA
AD  - 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.
FAU - Kolawole, Motunrayo
AU  - Kolawole M
AD  - 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.
FAU - Taruselli, Marcela T
AU  - Taruselli MT
AUID- ORCID: 0000-0002-7965-4335
AD  - 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.
FAU - Ajith, Siddarth
AU  - Ajith S
AD  - 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.
FAU - Dailey, Jordan M
AU  - Dailey JM
AD  - 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.
FAU - Kee, Sydney A
AU  - Kee SA
AD  - 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.
FAU - Haque, Tamara T
AU  - Haque TT
AUID- ORCID: 0000-0003-4436-9558
AD  - 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.
FAU - Barnstein, Brian O
AU  - Barnstein BO
AD  - 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.
FAU - McLeod, Jamie Josephine Avila
AU  - McLeod JJA
AD  - 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.
FAU - Caslin, Heather L
AU  - Caslin HL
AUID- ORCID: 0000-0002-7471-6779
AD  - 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.
FAU - Kiwanuka, Kasalina N
AU  - Kiwanuka KN
AD  - 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.
FAU - Fukuoka, Yoshihiro
AU  - Fukuoka Y
AD  - 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.
FAU - Le, Quang T
AU  - Le QT
AD  - 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.
FAU - Schwartz, Lawrence B
AU  - Schwartz LB
AD  - 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.
FAU - Straus, David B
AU  - Straus DB
AD  - 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.
FAU - Gewirtz, David A
AU  - Gewirtz DA
AD  - 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.
FAU - Martin, Rebecca K
AU  - Martin RK
AD  - 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.
FAU - Ryan, John J
AU  - Ryan JJ
AD  - 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.
LA  - eng
GR  - R01 AI138495/AI/NIAID NIH HHS/United States
GR  - R21 AI138494/AI/NIAID NIH HHS/United States
GR  - R25 GM090084/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20200520
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 4L066368AS (Fluvastatin)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Bone Marrow Cells/cytology
MH  - Cell Line
MH  - Cell Survival/drug effects
MH  - Fluvastatin/*pharmacology
MH  - Humans
MH  - Lipid Metabolism/drug effects
MH  - Mast Cells/*cytology/*drug effects/metabolism
MH  - Mice
PMC - PMC7306917
EDAT- 2020/05/22 06:00
MHDA- 2020/11/13 06:00
PMCR- 2021/07/01
CRDT- 2020/05/22 06:00
PHST- 2019/11/25 00:00 [received]
PHST- 2020/04/01 00:00 [accepted]
PHST- 2020/05/22 06:00 [pubmed]
PHST- 2020/11/13 06:00 [medline]
PHST- 2020/05/22 06:00 [entrez]
PHST- 2021/07/01 00:00 [pmc-release]
AID - jpet.119.264234 [pii]
AID - JPET_264234 [pii]
AID - 10.1124/jpet.119.264234 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2020 Jul;374(1):104-112. doi: 10.1124/jpet.119.264234. Epub 
      2020 May 20.