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.

Developmental transcriptome profiling of bovine muscle tissue reveals an abundant GosB that regulates myoblast proliferation and apoptosis

“…Proteins in the Bcl-2 family play a vital role in controlling intracellular Ca 2+ signals because of their ability to affect—either directly or indirectly—Ca 2+ storage in the endoplasmic reticulum by interacting with the inositol 1,4,5-trisphosphate receptor [ 32 , 34 ]. As an anti-apoptotic gene, Bcl-2 inhibits calcium release from the endoplasmic reticulum and mitochondrial calcium uptake, whereas Bax—a member of the pro-apoptotic Bcl-2 family—induces calcium release from the endoplasmic reticulum as well as mitochondrial Ca 2+ uptake [ 31 , 32 , 35 ]. In our present study, GosB increased the expression of Bcl-2, inhibited cytosolic and mitochondrial calcium accumulation, and protected C2C12 cells from apoptosis induced by acute increases in intracellular Ca 2+ concentrations.…”

Hypoxia induced mitogenic factor (HIMF) triggers angiogenesis by increasing interleukin-18 production in myoblasts

“…The AP-1 luciferase plasmid is originated from the background pLuc-MCS, as 5.7 kb in length, and it contains direct seven times repeats of the transcription recognition sequences, TGACTAA. For the reporter assay as described in previous studies 38 , cells were co-transfected with AP-1 luciferase (0.5 μg) and β-galactosidase expression vector (0.5 μg) for 24 h using Lipofectamine 2000 (Invitrogen), according to the manufacturer’s protocol. All results are obtained from four independent experiments.…”

Mechanism and Role of Endoplasmic Reticulum Stress in Osteosarcoma

“…ERS is often induced in solid tumors owing to glucose deficiency [ 66 ]. According to findings from reviews, GPR78 is more active in solid tumors such as breast tumors [ 173 ], fibrosarcoma [ 174 , 175 ], and chondrosarcoma [ 176 ]. Potential therapeutic agents targeting ERS in both chondrosarcoma and fibrosarcoma are primarily associated with GPR78.…”