Novel quinic acid derivative kz-41 prevents retinal endothelial cell apoptosis without inhibiting retinoblastoma cell death through p38 signaling

Qiuhua Zhang, Youde Jiang, Jordan Toutounchian, Matthew Wilson, Vanessa Morales-Tirado, Duane Miller, Charles Yates, Jena J. Steinle

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Abstract

PURPOSE. To determine whether a novel NF-jB inhibitor, KZ-41, can inhibit melphalan's actions on retinal endothelial cell (REC) inflammation and apoptosis, without eliminating the chemotherapeutic efficacy of melphalan on cell death of retinoblastoma cells (Y79). METHODS. RECs were cultured in M131 medium supplemented with growth factors and antibiotics. Once cells reached confluence, they were treated with or without 10 lM KZ-41, following treatment with 4 lg/mL melphalan. Cell proteins were extracted and analyzed for intracellular adhesion molecule 1 (ICAM-1) levels and Cell Death ELISA. RECs were also transfected with or without NF-jB siRNA or treated with SB202190 (p38 [mitogen activated protein kinase] MAPK inhibitor) before melphalan treatment to determine the involvement of NF-jB and p38 MAPK in REC apoptosis and ICAM-1 levels. We also cultured retinoblastoma cells (Y79) in RMPI-1640 medium supplemented with 20% fetal bovine serum and performed a Cell Death ELISA after melphalan {thorn} KZ-41 treatment to determine if the treatments altered melphalan's ability to promote cell death of Y79 cells. RESULTS. KZ-41 inhibited melphalan-stimulation of ICAM-1 levels and REC apoptosis, whereas KZ-41 did not alter melphalan's effects on Y79 cells. KZ-41's protective effects on REC were mediated through p38 MAPK activation. Although KZ-41 blocked both NF-jB- and p38 MAPK-dependent ICAM-1 stimulation; the p38 MAPK/ICAM-1 pathway appears to be the primary pathway involved in melphalan-induced REC apoptosis. CONCLUSIONS. KZ-41 protects REC against melphalan-induced upregulation of ICAM-1 and apoptosis through p38 MAPK-dependent pathways.

Original languageEnglish (US)
Pages (from-to)5937-5943
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume54
Issue number9
DOIs
StatePublished - Sep 23 2013

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Quinic Acid
Melphalan
Retinoblastoma
Cell Death
Endothelial Cells
Apoptosis
p38 Mitogen-Activated Protein Kinases
Enzyme-Linked Immunosorbent Assay
Therapeutics
Protein Kinase Inhibitors
Small Interfering RNA
Cultured Cells
Intercellular Signaling Peptides and Proteins
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

@article{834ecbccde2d4cd9a6ef6a85d898b632,
title = "Novel quinic acid derivative kz-41 prevents retinal endothelial cell apoptosis without inhibiting retinoblastoma cell death through p38 signaling",
abstract = "PURPOSE. To determine whether a novel NF-jB inhibitor, KZ-41, can inhibit melphalan's actions on retinal endothelial cell (REC) inflammation and apoptosis, without eliminating the chemotherapeutic efficacy of melphalan on cell death of retinoblastoma cells (Y79). METHODS. RECs were cultured in M131 medium supplemented with growth factors and antibiotics. Once cells reached confluence, they were treated with or without 10 lM KZ-41, following treatment with 4 lg/mL melphalan. Cell proteins were extracted and analyzed for intracellular adhesion molecule 1 (ICAM-1) levels and Cell Death ELISA. RECs were also transfected with or without NF-jB siRNA or treated with SB202190 (p38 [mitogen activated protein kinase] MAPK inhibitor) before melphalan treatment to determine the involvement of NF-jB and p38 MAPK in REC apoptosis and ICAM-1 levels. We also cultured retinoblastoma cells (Y79) in RMPI-1640 medium supplemented with 20{\%} fetal bovine serum and performed a Cell Death ELISA after melphalan {thorn} KZ-41 treatment to determine if the treatments altered melphalan's ability to promote cell death of Y79 cells. RESULTS. KZ-41 inhibited melphalan-stimulation of ICAM-1 levels and REC apoptosis, whereas KZ-41 did not alter melphalan's effects on Y79 cells. KZ-41's protective effects on REC were mediated through p38 MAPK activation. Although KZ-41 blocked both NF-jB- and p38 MAPK-dependent ICAM-1 stimulation; the p38 MAPK/ICAM-1 pathway appears to be the primary pathway involved in melphalan-induced REC apoptosis. CONCLUSIONS. KZ-41 protects REC against melphalan-induced upregulation of ICAM-1 and apoptosis through p38 MAPK-dependent pathways.",
author = "Qiuhua Zhang and Youde Jiang and Jordan Toutounchian and Matthew Wilson and Vanessa Morales-Tirado and Duane Miller and Charles Yates and Steinle, {Jena J.}",
year = "2013",
month = "9",
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doi = "10.1167/iovs.13-12326",
language = "English (US)",
volume = "54",
pages = "5937--5943",
journal = "Investigative Ophthalmology and Visual Science",
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number = "9",

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TY - JOUR

T1 - Novel quinic acid derivative kz-41 prevents retinal endothelial cell apoptosis without inhibiting retinoblastoma cell death through p38 signaling

AU - Zhang, Qiuhua

AU - Jiang, Youde

AU - Toutounchian, Jordan

AU - Wilson, Matthew

AU - Morales-Tirado, Vanessa

AU - Miller, Duane

AU - Yates, Charles

AU - Steinle, Jena J.

PY - 2013/9/23

Y1 - 2013/9/23

N2 - PURPOSE. To determine whether a novel NF-jB inhibitor, KZ-41, can inhibit melphalan's actions on retinal endothelial cell (REC) inflammation and apoptosis, without eliminating the chemotherapeutic efficacy of melphalan on cell death of retinoblastoma cells (Y79). METHODS. RECs were cultured in M131 medium supplemented with growth factors and antibiotics. Once cells reached confluence, they were treated with or without 10 lM KZ-41, following treatment with 4 lg/mL melphalan. Cell proteins were extracted and analyzed for intracellular adhesion molecule 1 (ICAM-1) levels and Cell Death ELISA. RECs were also transfected with or without NF-jB siRNA or treated with SB202190 (p38 [mitogen activated protein kinase] MAPK inhibitor) before melphalan treatment to determine the involvement of NF-jB and p38 MAPK in REC apoptosis and ICAM-1 levels. We also cultured retinoblastoma cells (Y79) in RMPI-1640 medium supplemented with 20% fetal bovine serum and performed a Cell Death ELISA after melphalan {thorn} KZ-41 treatment to determine if the treatments altered melphalan's ability to promote cell death of Y79 cells. RESULTS. KZ-41 inhibited melphalan-stimulation of ICAM-1 levels and REC apoptosis, whereas KZ-41 did not alter melphalan's effects on Y79 cells. KZ-41's protective effects on REC were mediated through p38 MAPK activation. Although KZ-41 blocked both NF-jB- and p38 MAPK-dependent ICAM-1 stimulation; the p38 MAPK/ICAM-1 pathway appears to be the primary pathway involved in melphalan-induced REC apoptosis. CONCLUSIONS. KZ-41 protects REC against melphalan-induced upregulation of ICAM-1 and apoptosis through p38 MAPK-dependent pathways.

AB - PURPOSE. To determine whether a novel NF-jB inhibitor, KZ-41, can inhibit melphalan's actions on retinal endothelial cell (REC) inflammation and apoptosis, without eliminating the chemotherapeutic efficacy of melphalan on cell death of retinoblastoma cells (Y79). METHODS. RECs were cultured in M131 medium supplemented with growth factors and antibiotics. Once cells reached confluence, they were treated with or without 10 lM KZ-41, following treatment with 4 lg/mL melphalan. Cell proteins were extracted and analyzed for intracellular adhesion molecule 1 (ICAM-1) levels and Cell Death ELISA. RECs were also transfected with or without NF-jB siRNA or treated with SB202190 (p38 [mitogen activated protein kinase] MAPK inhibitor) before melphalan treatment to determine the involvement of NF-jB and p38 MAPK in REC apoptosis and ICAM-1 levels. We also cultured retinoblastoma cells (Y79) in RMPI-1640 medium supplemented with 20% fetal bovine serum and performed a Cell Death ELISA after melphalan {thorn} KZ-41 treatment to determine if the treatments altered melphalan's ability to promote cell death of Y79 cells. RESULTS. KZ-41 inhibited melphalan-stimulation of ICAM-1 levels and REC apoptosis, whereas KZ-41 did not alter melphalan's effects on Y79 cells. KZ-41's protective effects on REC were mediated through p38 MAPK activation. Although KZ-41 blocked both NF-jB- and p38 MAPK-dependent ICAM-1 stimulation; the p38 MAPK/ICAM-1 pathway appears to be the primary pathway involved in melphalan-induced REC apoptosis. CONCLUSIONS. KZ-41 protects REC against melphalan-induced upregulation of ICAM-1 and apoptosis through p38 MAPK-dependent pathways.

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U2 - 10.1167/iovs.13-12326

DO - 10.1167/iovs.13-12326

M3 - Article

VL - 54

SP - 5937

EP - 5943

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 9

ER -