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Multiple Targets of 3-Dehydroxyceanothetric Acid 2-Methyl Ester to Protect Against Cisplatin-Induced Cytotoxicity in Kidney Epithelial LLC-PK1 Cells
Dahae Lee, 1 Ki Hyun Kim 1 , Won Yung Lee, 2 Chang-Eop Kim 2 , Sang Hyun Sung 3 , Kyo Bin Kang 4 , Ki Sung Kang 2 , M. Concepción Gimeno
1  School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea;(D.L.);(K.H.K.)
2  College of Korean Medicine, Gachon University, Seongnam 13120, Korea;(W.Y.L.);(C.-E.K.)
3  College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea
4  College of Pharmacy, Sookmyung Women’s University, Seoul 04310, Korea

Published: 01 March 2019 by MDPI in Molecules
MDPI, Volume 24; 10.3390/molecules24050878
Abstract: Chronic exposure to cisplatin, a potent anticancer drug, causes irreversible kidney damage. In this study, we investigated the protective effect and mechanism of nine lupane- and ceanothane-type triterpenoids isolated from jujube (Ziziphus jujuba Mill., Rhamnaceae) on cisplatin-induced damage to kidney epithelial LLC-PK1 cells via mitogen-activated protein kinase (MAPK) and apoptosis pathways. Cisplatin-induced LLC-PK1 cell death was most significantly reduced following treatment with 3-dehydroxyceanothetric acid 2-methyl ester (3DC2ME). Additionally, apoptotic cell death was significantly reduced. Expression of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 was markedly suppressed by 3DC2ME, indicating inhibition of the MAPK pathway. Treatment with 3DC2ME also significantly reduced expression of active caspase-8 and -3, Bcl-2-associated X protein (Bax), and B cell lymphoma 2 (Bcl-2), indicating the inhibition of apoptosis pathways in the kidneys. We also applied the network pharmacological analysis and identified multiple targets of 3DC2ME related to MAPK signaling pathway and apoptosis.
Keywords: apoptosis, cisplatin, MAPKs, nephrotoxicity
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