Nilotinib reduced the viability of human ovarian cancer cells via mitochondria-dependent apoptosis, independent of JNK activation. (March 2016)

• Record Type: Journal Article
• Authors: Chen, Tze-Chien; Yu, Ming-Chih; Chien, Chih-Chiang; Wu, Ming-Shun; Lee, Yu-Chieh; Chen, Yen-Chou
• Is Part Of: Toxicology in vitro. Volume 31(2016)
• Page Start: 1
• Page End: 11
• Publication Date: 2016-03
• Subjects: AMN nilotinib -- BCIP 5-bromo-4-chloro-3-indolyl phosphate -- Bcl-2 B-cell lymphoma 2 -- DCFH-DA 2′, 7′-dichlorofluorescein diacetate -- DMSO dimethyl sulfoxide -- EGF epidermal growth factor -- ELISA enzyme-linked immunosorbent assay -- ERK extracellular signal-regulated kinase -- H2O2 hydrogen peroxide -- JNK c-Jun N-terminal kinase -- MAPK mitogen-activated protein kinase -- MMP mitochondrial membrane potential -- MTT 3-(4, 5, -dimethylthiazol)-2-yl-2, 5-diphenyltetrazolium bromide -- NAC N-acetyl-l-cysteine -- NBT nitroblue tetrazolium -- PARP1 poly(ADP-ribose) polymerase 1 -- Cyt c cytochrome c -- ROS reactive oxygen species -- SDS sodium dodecylsulfate -- SORA sorafenib -- SP SP600125 -- STI imatinib -- TKI tyrosine kinase inhibitor -- DiOC6 3, 3′-dihexyloxacarbocyanine iodide; Nilotinib -- Apoptosis -- Caspase-3 -- Mitochondria -- c-Jun N-terminal kinase -- Reactive oxygen species; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2015.11.002
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: Nilotinib (AMN) induces apoptosis in various cancer cells; however the effect of AMN on human ovarian cancer cells is still unclear. A reduction in cell viability associated with the occurrence of apoptotic characteristics was observed in human SKOV-3 ovarian cancer cells under AMN but not sorafenib (SORA) or imatinib (STI) stimulation. Activation of apoptotic pathway including increased caspase (Casp)-3 and poly(ADP-ribose) polymerase 1 (PARP1) protein cleavage by AMN was detected with disrupted mitochondrial membrane potential (MMP) accompanied by decreased Bcl-2 protein and increased cytosolic cytochrome (Cyt) c/cleaved Casp-9 protein expressions was found, and AMN-induced cell death was inhibited by peptidyl Casp inhibitors, VAD, DEVD and LEHD. Increased phosphorylated c-Jun N-terminal kinase (JNK) protein expression was detected in AMN- but not SORA- or STI-treated SKOV-3 cells, and the JNK inhibitors, SP600125 and JNKI, showed slight but significant enhancement of AMN-induced cell death in SKOV-3 cells. The intracellular peroxide level was elevated by AMN and H2 O2, and N-acetylcysteine (NAC) prevented H2 O2 - but not AMN-induced peroxide production and apoptosis in SKOV-3 cells. AMN induction of apoptosis with increased intracellular peroxide production and JNK protein phosphorylation was also identified in human A2780 ovarian cancer cells, cisplatin-resistant A2780CP cells, and clear ES-2 cells. The evidence supporting AMN effectively reducing the viability of human ovarian cancer cells via mitochondrion-dependent apoptosis is provided. Highlights: Nilotinib induced apoptosis in various human ovarian cancer cells. Disrupted mitochondrial membrane potentiation leads to apoptosis by nilotinib. Increased intracellular peroxide and JNK by nilotinib NAC and JNK inhibitors did not inhibit apoptosis induced by nilotinib. A more potent cytotoxicity on ovarian cancer than non-cancerous cells by nilotinib