Novel quinic acid derivative KZ-41 prevents retinal endothelial cell apoptosis without inhibiting retinoblastoma cell death through p38 signaling.
OBJECTIVE
To determine whether a novel NF-κB 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 μM KZ-41, following treatment with 4 μg/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-κB siRNA or treated with SB202190 (p38 [mitogen activated protein kinase] MAPK inhibitor) before melphalan treatment to determine the involvement of NF-κB 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 + 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-κB- 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.
Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Qiuhua
Q
Zhang
Youde
Y
Jiang
Jordan
J
Toutounchian
Matthew W
MW
Wilson
Vanessa
V
Morales-Tirado
Duane D
DD
Miller
C Ryan
CR
Yates
Jena J
JJ
Steinle
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D011801:Quinic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D019572:Retinal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D012175:Retinoblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
C569814:KZ 41 compound; D011801:Quinic Acid
KZ-41; NF-κB; Y79; cell death; inflammation; retinal endothelial cell