Cytotoxicity of α-tocopheryl succinate, malonate and oxalate in normal and cancer cells in vitro and their anti-cancer effects on mouse melanoma in vivo
Cytotoxicity of α-tocopheryl succinate, malonate and oxalate in normal and cancer cells in vitro and their anti-cancer effects on mouse melanoma in vivo
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DOI：
10.3177/jnsv.51.392
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发表时间：
2005-12-01
影响因子：
1.6
通讯作者：
Fukuzawa, K
中科院分区：
文献类型：
--
作者：
Kogure, K;Manabe, S;Fukuzawa, K
已知α-生育酚琥珀酸酯（TS）在癌细胞中选择性诱导细胞凋亡，其作为化疗剂已经引起关注。最近，我们发现在所测试的α-生育酚酯中，α-生育酚丙二酸酯（TM）和α-生育酚草酸酯（TO）具有高的生育活性以及TS。本研究以小鼠黑色素瘤B16-F1细胞为模型，研究了它们对正常细胞和肿瘤细胞的体外细胞毒作用特点，以及对小鼠黑色素瘤B16-F1细胞的体内抗肿瘤作用。体外细胞毒作用顺序为TO >= TM >> TS。添加外源性超氧化物歧化酶（SOD）和抗氧化剂N-乙酰半胱氨酸（NAC）抑制TS和TM-，但不TO-诱导的细胞死亡。观察到TS对癌细胞的选择性细胞毒作用，但TM或TO没有。c-Jun N-末端激酶（JNK）抑制剂II阻止TS诱导的细胞死亡，但不能阻止TM或TO诱导的细胞死亡。给接种黑色素瘤B16-F1细胞的小鼠静脉注射囊泡TS和TM可防止肿瘤生长并延长平均存活时间，但TO给药由于其急性高毒性而杀死小鼠。根据这些结果，我们讨论了它们对肿瘤细胞的体外选择性细胞毒作用和体内抗癌作用的特点。
alpha-Tocopheryl succinate (TS), which is known to induce apoptosis selectively in cancer cells, has attracted attention as a chemotherapeutic agent. Recently, we found that alpha-tocopheryl malonate (TM) and alpha-tocopheryl oxalate (TO), among the alpha-tocopheryl esters tested, have high apoptogenic activity as well as TS. In this study, we investigated the characteristics of their cytotoxicity on normal cells and cancer cells in vitro, and their anticancer effects on mice inoculated with melanoma B16-F1 cells in vivo. The order of in vitro cytotoxicity was TO >= TM >> TS in all cell lines examined. Addition of exogenous superoxide dismutase (SOD) and the antioxidant N-acetyl cysteine (NAC) inhibited TS- and TM- but not TO-induced cell deaths. A selective cytotoxic effect on cancer cells was observed with TS but not with TM or TO. c-Jun N-terminal kinase (JNK) inhibitor II prevented cell death induced by TS but did not prevent cell deaths induced either by TM or TO. Intravenous administration of vesiculated TS and TM to mice inoculated with melanoma B16-F1 cells prevented tumor growth and enhanced the mean survival time, but TO administration killed the mice due to its acute high toxicity. From these results, we discussed the characteristics of their selective cytotoxicity toward tumor cells in vitro and anti-cancer effects in vivo.