FPipTB, a benzimidazole derivative, induces chondrosarcoma cell apoptosis via endoplasmic reticulum stress and apoptosis signal-regulating kinase 1

Ju Fang Liu, Chih Shiang Chang, Yi Chin Fong, Sheng Chu Kuo, Chih Hsin Tang

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

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 Ca2+ 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.

Original languageEnglish
Pages (from-to)315-326
Number of pages12
JournalMolecular Carcinogenesis
Volume51
Issue number4
DOIs
Publication statusPublished - Apr 1 2012

Keywords

  • ASK1
  • Benzimidazole
  • Chondrosarcoma
  • ER stress

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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