Chondrosarcoma is a malignant primary bone tumor that responds poorly to both chemotherapy and radiation therapy. The aim of this study was to elucidate the mechanism of the novel Combretastatin A‐4 derivative, 2‐(furanyl)‐5‐(pyrrolidinyl)‐1‐(3,4,5‐trimethoxybenzyl)benzoimidazole (FPTB)‐induced human chondrosarcoma cells apoptosis. FPTB induced cell apoptosis in human chondrosarcoma cell line but not primary chondrocytes. FPTB induced up‐regulation of Bax and Bak, down‐regulation of Bcl‐2 and Bcl‐XL and dysfunction of mitochondria in chondrosarcoma. FPTB also triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosol‐calcium levels. We found that FPTB increased glucose‐regulated proteins (GRP)78 but not GRP94 expression. In addition, treatment of cells with FPTB induced calpain expression and activity. Transfection of cells with GRP78 or calpain siRNA reduced FPTB‐mediated cell apoptosis. Therefore, FPTB‐induced apoptosis in chondrosarcoma cells through the mitochondria dysfunction and involves caspase‐9 and caspase‐3‐mediated mechanism. FPTB also induced cell death mediated by increasing ER stress, GPR78 activation, and Ca2+ release, which subsequently triggers calpain, caspase‐12 and caspase‐3 activity, resulting in apoptosis. J. Cell. Biochem. 112: 453–462, 2011. © 2010 Wiley‐Liss, Inc.