Dataset Information

A novel benzofuran derivative, ACDB, induces apoptosis of human chondrosarcoma cells through mitochondrial dysfunction and endoplasmic reticulum stress.

ABSTRACT: Chondrosarcoma is one of the bone tumor with high mortality in respond to poor radiation and chemotherapy treatment. Here, we analyze the antitumor activity of a novel benzofuran derivative, 2-amino-3-(2-chlorophenyl)-6-(4-dimethylaminophenyl)benzofuran-4-yl acetate (ACDB), in human chondrosarcoma cells. ACDB increased the cell apoptosis of human chondrosarcomas without harm in chondrocytes. ACDB also enhanced endoplasmic reticulum (ER) stress, which was characterized by varieties in the cytosolic calcium levels and induced the expression of glucose-regulated protein (GRP) and calpain. Furthermore, the ACDB-induced chondrosarcoma apoptosis was associated with the upregulation of the B cell lymphoma-2 (Bcl-2) family members including pro- and anti-apoptotic proteins, downregulation of dysfunctional mitochondria that released cytochrome C, and subsequent activation of caspases-3. In addition, the ACDB-mediated cellular apoptosis was suppressed by transfecting cells with glucose-regulated protein (GRP) and calpain siRNA or treating cells with ER stress chelators and caspase inhibitors. Interestingly, animal experiments illustrated a reduction in the tumor volume following ACDB treatment. Together, these results suggest that ACDB may be a novel tumor suppressor of chondrosarcoma, and this study demonstrates that the novel antitumor agent, ACDB, induced apoptosis by mitochondrial dysfunction and ER stress in human chondrosarcoma cells in vitro and in vivo.

SUBMITTER: Su CM

PROVIDER: S-EPMC5347786 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A novel benzofuran derivative, ACDB, induces apoptosis of human chondrosarcoma cells through mitochondrial dysfunction and endoplasmic reticulum stress.

Su Chen-Ming CM Chen Chien-Yu CY Lu Tingting T Sun Yi Y Li Weimin W Huang Yuan-Li YL Tsai Chun-Hao CH Chang Chih-Shiang CS Tang Chih-Hsin CH

Oncotarget 20161201 50

Chondrosarcoma is one of the bone tumor with high mortality in respond to poor radiation and chemotherapy treatment. Here, we analyze the antitumor activity of a novel benzofuran derivative, 2-amino-3-(2-chlorophenyl)-6-(4-dimethylaminophenyl)benzofuran-4-yl acetate (ACDB), in human chondrosarcoma cells. ACDB increased the cell apoptosis of human chondrosarcomas without harm in chondrocytes. ACDB also enhanced endoplasmic reticulum (ER) stress, which was characterized by varieties in the cytosol ...[more]

PMID: 27835579

Similar Datasets

Project description:Lithocholic acid (LCA) is a secondary bile acid that is selectively toxic to human neuroblastoma, breast and prostate cancer cells, whilst sparing normal cells. We previously reported that LCA inhibited cell viability and proliferation and induced apoptosis and necrosis of androgen-dependent LNCaP and androgen-independent PC-3 human prostate cancer cells. In the present study, we investigated the roles of endoplasmic reticulum (ER) stress, autophagy and mitochondrial dysfunction in the toxicity of LCA in PC-3 and autophagy deficient, androgen-independent DU-145 cells. LCA induced ER stress-related proteins, such as CCAAT-enhancer-binding protein homologous protein (CHOP), and the phosphorylation of eukaryotic initiation factor 2-alpha (p-eIF2α) and c-Jun N-terminal kinases (p-JNK) in both cancer cell-types. The p53 upregulated modulator of apoptosis (PUMA) and B cell lymphoma-like protein 11 (BIM) levels were decreased at overtly toxic LCA concentrations, although PUMA levels increased at lower LCA concentrations in both cell lines. LCA induced autophagy-related conversion of microtubule-associated proteins 1A/1B light chain 3B (LC3BI-LC3BII), and autophagy-related protein ATG5 in PC-3 cells, but not in autophagy-deficient DU-145 cells. LCA (>10 µM) increased levels of reactive oxygen species (ROS) concentration-dependently in PC-3 cells, whereas ROS levels were not affected in DU-145 cells. Salubrinal, an inhibitor of eIF2α dephosphorylation and ER stress, reduced LCA-induced CHOP levels slightly in PC-3, but not DU-145 cells. Salubrinal pre-treatment increased the cytotoxicity of LCA in PC-3 and DU-145 cells and resulted in a statistically significant loss of cell viability at normally non-toxic concentrations of LCA. The late-stage autophagy inhibitor bafilomycin A1 exacerbated LCA toxicity at subtoxic LCA concentrations in PC-3 cells. The antioxidant α-tocotrienol strongly inhibited the toxicity of LCA in PC-3 cells, but not in DU-145 cells. Collectively, although LCA induces autophagy and ER stress in PC-3 cells, these processes appear to be initially of protective nature and subsequently consequential to, but not critical for the ROS-mediated mitochondrial dysfunction and cytotoxicity of LCA. The full mechanism of LCA-induced mitochondrial dysfunction and cytotoxicity in the similarly sensitive DU-145 cells remains to be elucidated.

Project description:The ongoing Goose astrovirus (GoAstV) epidemic, which primarily infects goslings causing severe liver damage, has inflicted considerable damage on the poultry industry. Endoplasmic reticulum stress (ERS) is a significant modulator of several viral infections, while severe ERS may result in apoptosis. This study examined the roles and possible mechanisms of ERS and apoptosis in GoAstV-induced liver injury in goslings. Two hundred Xingguo gray geese were chosen and randomly separated into two groups (Con and Dis). The Dis group received a subcutaneous injection of GoAstV genotype 2 (GoAstV-2) JX01 (2 × 106 TCID50/0.2 mL), whereas the Con group received a subcutaneous injection of 0.2 mL physiological saline, both at 1 day of life. Subsequent analyses demonstrate that the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) increased following GoAstV infection. Hematoxylin and eosin (HE) staining revealed swollen and ruptured hepatocytes, with significant inflammatory cell infiltration. Electron microscopy revealed expansion of the endoplasmic reticulum (ER) and aggregation of chromatin at the periphery. TUNEL testing further demonstrated an increase in the quantity of positive cells. RT-qPCR and Western blot analyses indicated that GoAstV infection enhanced the expression of ER Ca2+ release channels (IP3R and RYR) and calmodulin-dependent protein kinase II (CaMKII), while decreasing the expression of ER Ca2+ uptake channels (SERCA). Further, GoAstV infection activated ERS-related factors, including GRP78, IRE1α, PERK, ATF6, eIF2α, ATF4, CHOP, TRAF2, and JNK, induced the expression of pro-apoptotic factors (Caspase-3, Caspase-9, and Bax), and inhibited the mRNA and protein expression of the anti-apoptotic factor Bcl-2. Correlation analysis further revealed a potential relationship among ERS gene expression, apoptotic gene expression, and liver injury. In summary, GoAstV infection can lead to liver injury by interfering with ER Ca2+ homeostasis, exacerbating ERS and inducing hepatocyte apoptosis.

Dataset Information

A novel benzofuran derivative, ACDB, induces apoptosis of human chondrosarcoma cells through mitochondrial dysfunction and endoplasmic reticulum stress.

Publications

A novel benzofuran derivative, ACDB, induces apoptosis of human chondrosarcoma cells through mitochondrial dysfunction and endoplasmic reticulum stress.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets