A novel benzofuran derivative, ACDB, induces apoptosis of human chondrosarcoma cells through mitochondrial dysfunction and endoplasmic reticulum stress.
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.
Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China.|Graduate Institute of Basic Medical Science, China Medical University, Taichung Taiwan.
Chen-Ming
CM
Su
Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
Chien-Yu
CY
Chen
Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China.
Tingting
T
Lu
Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China.
Yi
Y
Sun
Department of Cardiology, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China.
Weimin
W
Li
Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.
Yuan-Li
YL
Huang
School of Medicine, China Medical University, Taichung, Taiwan.|Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan.
Chun-Hao
CH
Tsai
Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
Chih-Shiang
CS
Chang
Graduate Institute of Basic Medical Science, China Medical University, Taichung Taiwan.|Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.|Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.
Chih-Hsin
CH
Tang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001572:Benzofurans / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002813:Chondrosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001572:Benzofurans; D017382:Reactive Oxygen Species; D002154:Calpain
apoptosis; benzofuran; chondrosarcoma; endoplasmic reticulum (ER) stress; mitochondrial dysfunction