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FPipTB, a benzimidazole derivative, induces chondrosarcoma cell apoptosis via endoplasmic reticulum stress and apoptosis signal‐regulating kinase 1
Author(s) -
Liu JuFang,
Chang ChihShiang,
Fong YiChin,
Kuo ShengChu,
Tang ChihHsin
Publication year - 2012
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20787
Subject(s) - apoptosis , endoplasmic reticulum , biology , microbiology and biotechnology , p38 mitogen activated protein kinases , unfolded protein response , ask1 , downregulation and upregulation , chondrosarcoma , programmed cell death , signal transduction , intracellular , cancer research , xiap , kinase , cytosol , protein kinase a , caspase , mitogen activated protein kinase kinase , biochemistry , pathology , medicine , gene , enzyme
Abstract Chondrosarcoma is the second most common primary bone tumor and it responds poorly to both chemotherapy and radiation treatment. In this study, we investigated the anticancer effects of a new benzimidazole derivative, 2‐(furanyl)‐5‐(piperidinyl)‐ (3,4,5‐trimethoxybenzyl) benzimidazole (FPipTB) in human chondrosarcoma cells. FPipTB‐induced apoptosis in human chondrosarcoma cell lines (JJ012 and SW1353) but not in primary chondrocytes. Furthermore, it triggered endoplasmic reticulum (ER) stress, which was characterized by changes in cytosolic calcium levels. Treatment of chondrosarcoma cells with FPipTB was associated with increased intracellular levels of ASK1, p38, p53, and Bax, followed by release of cytochrome c from mitochondria and activation of caspases. It is also known that ER stress activates apoptosis signal‐regulating kinase 1 (ASK1), which mediates activation of JNK and p38 pathways. We also found that FPipTB‐induced p38 and p53 phosphorylation and upregulated Bax expression. To study the mechanism of Bax upregulation, we determined that Bax promoter activity was increased in FPipTB‐treated cells, leading to an increase in intracellular levels of Bax. In addition, cell treated with Ca 2+ chelator or p38 inhibitor showed reduced transcriptional activity. The results further suggest that FPipTB triggered ER stress, as indicated by changes in cytosolic calcium levels and activated the ASK1‐MKK3/6‐p38‐p53‐Bax pathway, causing chondrosarcoma cell death. Importantly, animal studies revealed a dramatic 40% reduction in tumor volume after 21 d of treatment. Thus, FPipTB may be a novel anticancer agent for the treatment of chondrosarcoma. © 2011 Wiley Periodicals, Inc.