School of Chinese Medicine, China Medical University, Taichung, Taiwan.
Mol Carcinog. 2011 Oct;50(10):791-803. doi: 10.1002/mc.20749. Epub 2011 Mar 3.
Chondrosarcoma is a malignant primary bone tumor that responds poorly to both chemotherapy and radiation therapy. This study is the first to investigate the anti-cancer effects of the new benzimidazole derivative (5-methyl-2(pyridine-3-yl)-1-(3,4,5-trimethoxybenzyl)benzimidazole; MPTB) in human chondrosarcoma cells. MPTB-induced cell apoptosis in two human chondrosarcoma cell lines, JJ012 and SW1353 but not in primary chondrocytes. MPTB-induced upregulation of Bax and Bak and dysfunction of mitochondria in chondrosarcoma. MPTB triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosol calcium levels, and increased glucose-regulated protein (GRP) expression. MPTB also increased calpain expression. Transfection of cells with GRP78 or calpain siRNA reduced MPTB-mediated cell apoptosis in JJ012 cells. Importantly, animal studies have revealed a dramatic 44% reduction in tumor volume after 21 d of treatment. This study demonstrates novel anti-cancer activity of MPTB against human chondrosarcoma cells and in murine tumor models.
软骨肉瘤是一种恶性原发性骨肿瘤，对化疗和放疗均反应不佳。本研究首次探讨了新型苯并咪唑衍生物（5-甲基-2（吡啶-3-基）-1-（3,4,5-三甲氧基苄基）苯并咪唑；MPTB）在人软骨肉瘤细胞中的抗癌作用。MPTB 诱导两种人软骨肉瘤细胞系 JJ012 和 SW1353 而不是原代软骨细胞发生细胞凋亡。MPTB 诱导 Bax 和 Bak 的上调以及软骨肉瘤中线粒体功能障碍。MPTB 引发内质网（ER）应激，表现为细胞质钙水平的变化和葡萄糖调节蛋白（GRP）表达增加。MPTB 还增加了钙蛋白酶的表达。用 GRP78 或钙蛋白酶 siRNA 转染细胞可减少 JJ012 细胞中 MPTB 介导的细胞凋亡。重要的是，动物研究表明，治疗 21 天后肿瘤体积显著减少了 44%。本研究证明了 MPTB 对人软骨肉瘤细胞和小鼠肿瘤模型的新型抗癌活性。
