Morshed Sufi Reza M D, Hashimoto Ken, Murotani Yukie, Kawase Masami, Shah Anamik, Satoh Kazue, Kikuchi Hirotaka, Nishikawa Hirofumi, Maki Jun, Sakagami Hiroshi
Meikai Pharmaco-Medical Laboratory (MPL), Meikai University School of Dentistry, Sakado, Saitama, Japan.
Anticancer Res. 2005 May-Jun;25(3B):2033-8.
In search of compounds which show tumor-specific cytotoxic activity, two 3,5-dibenzoyl-1, 4-dihydropyridines (GB5, GB12) were found to show one or two orders higher cytotoxic activity against human tumor cell lines (squamous cell carcinoma HSC-2, HSC-3, submandibular gland carcinoma HSG, promyelocytic leukemia HL-60) than human normal cells (gingival fibroblast HGF, pulp cells HPC, periodontal ligament fibroblasts HPLF). GB5 and GB12 weakly induced several apoptosis-associated properties, such as internucleosomal DNA fragmentation, and activation of caspases -3, -8 and -9, in both HL-60 and HSC-2 cells. Western blot analysis showed that GB5 and GB12 transiently increased the expression of both anti-apoptotic protein (Bcl-2) and proapoptotic proteins (Bax and Bad) in HL-60 cells. ESR spectroscopy showed these compounds did not produce any detectable amount of radicals, nor scavenged superoxide (generated by hypoxanthine-xanthine oxidase reaction) or nitric oxide (generated by 1-hydroxy-2-oxo-3-(N-3-methyl-3-aminopropyl)-3-methyl-1-triazene), suggesting that the induction of cytotoxic action is not via a radical-mediated reaction. The present study suggests that GB5 and GB12 may induce non-apoptotic cell death in tumor cell lines.
为了寻找具有肿瘤特异性细胞毒活性的化合物，发现两种3,5-二苯甲酰基-1,4-二氢吡啶（GB5、GB12）对人肿瘤细胞系（鳞状细胞癌HSC-2、HSC-3、下颌下腺癌HSG、早幼粒细胞白血病HL-60）的细胞毒活性比人正常细胞（牙龈成纤维细胞HGF、牙髓细胞HPC、牙周膜成纤维细胞HPLF）高一个或两个数量级。GB5和GB12在HL-60和HSC-2细胞中均微弱诱导了几种凋亡相关特性，如核小体间DNA片段化以及半胱天冬酶-3、-8和-9的激活。蛋白质免疫印迹分析表明，GB5和GB12可使HL-60细胞中抗凋亡蛋白（Bcl-2）和促凋亡蛋白（Bax和Bad）的表达短暂增加。电子自旋共振光谱显示，这些化合物不会产生任何可检测到的自由基，也不会清除超氧化物（由次黄嘌呤-黄嘌呤氧化酶反应产生）或一氧化氮（由1-羟基-2-氧代-3-(N-3-甲基-3-氨丙基)-3-甲基-1-三氮烯产生），这表明细胞毒作用的诱导不是通过自由基介导的反应。本研究表明，GB5和GB12可能在肿瘤细胞系中诱导非凋亡性细胞死亡。
