Suppression of Tumor Growth In vivo by the Mitocan α-tocopheryl Succinate Requires Respiratory Complex II
Suppression of Tumor Growth In vivo by the Mitocan α-tocopheryl Succinate Requires Respiratory Complex II
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DOI：
10.1158/1078-0432.ccr-08-2439
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发表时间：
2009-03-01
影响因子：
11.5
通讯作者：
Neuzil, Jiri
中科院分区：
文献类型：
--
作者：
Dong, Lan-Feng;Freeman, Ruth;Neuzil, Jiri
目的：维生素E类似物是一种有效的新型抗癌药物。本研究的目的是阐明以α-生育酚琥珀酸酯(α-TOS)为代表的这些药物在体内抑制肿瘤的细胞靶点，重点是线粒体复合体II(CII)。实验设计：用H-RAS转化具有功能、功能障碍和重组的CII的中国仓鼠肺成纤维细胞。结果：与CII功能障碍细胞不同，CII功能细胞和CII重组细胞对α-TOS的反应是通过产生活性氧和执行细胞凋亡来实现的。来自这些细胞系的肿瘤对α-TOS的反应是相互作用的。因此，CII功能性和CII重组肿瘤的生长受到该药的强烈抑制，并伴随着高水平的肿瘤细胞凋亡诱导。另一方面，α-TOS不能抑制CII功能障碍的肿瘤。结论：我们在这份报告中记录了一个新的范例，根据这个范例，线粒体CII在人类肿瘤中很少发生突变，是维生素E类似物组中抗癌药物的一个可能的靶点，为临床试验提供支持。
Purpose: Vitamin E analogues are potent novel anticancer drugs. The purpose of this study was to elucidate the cellular target by which these agents, represented by alpha-tocopoheryl succinate (alpha-TOS), suppress tumors in vivo, with the focus on the mitochondrial complex II (CII).Experimental Design: Chinese hamster lung fibroblasts with functional, dysfunctional, and reconstituted CII were transformed using H-Ras. The cells were then used to form xenografts in immunocompromized mice, and response of the cells and the tumors to alpha-TOS was studied.Results: The CII-functional and CII-reconstituted cells, unlike their CII-dysfunctional counterparts, responded to alpha-TOS by reactive oxygen species generation and apoptosis execution. Tumors derived from these cell lines reciprocated their responses to alpha-TOS. Thus, growth of CII-functional and CII-reconstituted tumors was strongly suppressed by the agent, and this was accompanied by high level of apoptosis induction in the tumor cells. On the other hand, alpha-TOS did not inhibit the CII-dysfuntional tumors.Conclusions: We document in this report a novel paradigm, according to which the mitochondrial CII, which rarely mutates in human neoplasias, is a plausible target for anticancer drugs from the group of vitamin E analogues, providing support for their testing in clinical trials.