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Nimbolide induced apoptosis by activating ERK‐mediated inhibition of c‐IAP1 expression in human hepatocellular carcinoma cells
Author(s) -
Hsueh KuanChun,
Lin ChiaLiang,
Tung JaiNien,
Yang ShunFa,
Hsieh YiHsien
Publication year - 2018
Publication title -
environmental toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.813
H-Index - 77
eISSN - 1522-7278
pISSN - 1520-4081
DOI - 10.1002/tox.22576
Subject(s) - xiap , apoptosis , mapk/erk pathway , in vivo , poly adp ribose polymerase , microbiology and biotechnology , biology , caspase , hepatocellular carcinoma , inhibitor of apoptosis , programmed cell death , cell growth , cancer research , chemistry , signal transduction , biochemistry , gene , polymerase
Nimbolide is one of the major compounds from the leaves and flowers of the neem tree and exhibits antitumor properties on various cancer cells. However, no report has shown that nimbolide induces apoptosis in vitro and in vivo in human hepatocellular carcinoma cells. Our results indicated that it inhibited cell growth in Huh‐7 and PLC/PRF/5 cells. We also found that nimbolide induced cell death through the induction of G2/M phase arrest and mitochondrial dysfunction, accompanied by the increased expression of cleaved caspase‐7, caspase‐9, caspase‐3, caspase‐PARP, and Bax and decreased expression of Mcl‐1 and Bcl‐2. A human apoptosis antibody array analysis demonstrated that inhibition of the apoptosis family proteins (XIAP, c‐IAP1, and c‐IAP2) was one of the major targets of nimbolide. Additionally, nimbolide sustained activation of ERK expression. Moreover, pretreatment with U0126 (MEK inhibitor) markedly abolished nimbolide‐inhibited cell viability, induced cell apoptosis, ERK phosphorylation, cleaved caspase‐9, caspase‐3, cleaved‐PARP activation, and increased c‐IAP1 expression in Huh‐7 cells. An in vivo study showed that nimbolide significantly reduced Huh‐7 tumor growth and weight in a xenograft mouse model. This study indicated the antitumor potential of nimbolide in human hepatocellular carcinoma cells.