Dosing Time-Dependent Changes in the Anti-tumor Effect of xCT Inhibitor Erastin in Human Breast Cancer Xenograft Mice
Dosing Time-Dependent Changes in the Anti-tumor Effect of xCT Inhibitor Erastin in Human Breast Cancer Xenograft Mice
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DOI：
10.1248/bpb.b19-00546
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发表时间：
2019-11-01
影响因子：
2
通讯作者：
Ohdo, Shigehiro
中科院分区：
文献类型：
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作者：
Shiromizu, Shoya;Yamauchi, Tomoaki;Ohdo, Shigehiro
与正常细胞相比，癌细胞的生长更依赖于各种类型的氨基酸，因此预防对氨基酸的需求已被认为是癌症治疗的策略。在本研究中，我们发现在培养基中剥夺半胱氨酸（Cys）可以阻止各种类型的人类癌细胞系的生长。Cys在培养基中很容易转化为胱氨酸（Cys），并通过胱氨酸/谷氨酸转运蛋白（xCT）进入细胞。将掺入的Cys分解成Cys，用于合成抑制活性氧诱导的细胞损伤的谷胱甘肽。因此，我们研究了选择性xCT抑制剂erastin是否能阻止人类癌细胞系的生长。结果，擦除素显著地阻止了各种类型的人类癌细胞的增殖。其中，MDA-MB-231乳腺癌细胞被鉴定为对橡皮蛋白最敏感的细胞。为了研究擦除素对小鼠肿瘤生长的抑制作用，我们将MDA-MB-231乳腺癌细胞植入BALB/c裸鼠体内，置于标准化光/暗循环条件下。在光期给药可明显抑制小鼠植入肿瘤的生长，而在暗期给药则不能抑制肿瘤的生长。erastin诱导的半胱氨酸/半胱氨酸剥夺的剂量时间依赖性与其抗肿瘤作用密切相关。我们目前的研究结果表明，通过优化给药方案可以提高erastin对荷瘤小鼠的抗肿瘤作用。
Growth of cancer cells is more highly dependent on various types of amino acids than that of normal cells, and thus prevention of amino acid requirement has been recognized as strategies for cancer therapies. In this study, we found that deprivation of cysteine (Cys) in culturing media prevented the growth of various types of human cancer cell lines. Cys is easily converted to cystine (Cys Cys) in media and uptaken into cells by cystine/glutamate transporter (xCT). The incorporated Cys Cys is decomposed into Cys, and used for synthesis of glutathione that suppresses reactive oxygen species-induced cell damage. Therefore, we examined whether a selective xCT inhibitor erastin prevented the growth of human cancer cell lines. As a result, erastin significantly prevented the proliferation of various types of human cancer cells. Among them, MDA-MB-231 breast cancer cells were identified as the most erastin-sensitive cells. To investigate the ability of erastin to prevent growth of tumor in mice, MDA-MB-231 breast cancer cells were implanted into BALB/c nude female mice kept under standardized light/dark cycle conditions. The growth of tumor implanted in mice was significantly suppressed by administration of erastin during the light phase, whereas its administration during the dark phase failed to suppress the tumor growth. The dosing time-dependency of erastin-induced cystine/cysteine deprivation was closely related to that of its anti-tumor effects. Our present findings suggest that the anti-tumor efficacy of erastin in tumor-bearing mice is improved by optimizing the dosing schedule.