l-Type amino acid transporter 1 inhibitors inhibit tumor cell growth
l-Type amino acid transporter 1 inhibitors inhibit tumor cell growth
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DOI：
10.1111/j.1349-7006.2009.01386.x
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发表时间：
2010-01-01
期刊：
影响因子：
5.7
通讯作者：
Endou, Hitoshi
中科院分区：
文献类型：
--
作者：
Oda, Koji;Hosoda, Noriko;Endou, Hitoshi
大多数肿瘤细胞膜过表达l型氨基酸转运蛋白1，而正常细胞膜含有l型氨基酸转运蛋白2;两者都是Na+非依赖性氨基酸转运蛋白。因此，选择性抑制l型氨基酸转运蛋白1的化合物为研究人员提供了一种新型癌症分子靶点。合成化学的努力和体外筛选已经产生了多种具有高体外型氨基酸转运蛋白1选择性的新型化合物; KYT-0353就是这样一种化合物。目前的研究表明，KYT-0353抑制人结肠癌HT-29细胞的14 C-亮氨酸摄取和细胞生长; IC（50）分别为0.06 μ m和4.1 μ m。KYT-0353还抑制表达l-型氨基酸转运蛋白1的小鼠肾近端小管细胞的14 C-亮氨酸摄取，并抑制细胞生长; IC（50）分别为0.14 μ m和16.4 μ m。与对照动物相比，静脉给药KYT-0353（12.5 mg/kg和25.0 mg/kg）对移植到裸鼠的HT-29肿瘤显示出统计学显著的生长抑制，最大抑制率分别为65.9%和77.2%。12.5 mg/kg和25.0 mg/kg剂量组的体重随时间增加（安全性指标）轻微降低，最大比率分别为3.7%（第2天）和6.3%（第11天）。因此，KYT-0353在体外和体内均显示出对HT-29细胞的显著生长抑制作用，而其仅引起轻微的体重下降。因此，KYT-0353似乎具有作为新型抗肿瘤剂的潜力，推测是通过选择性体内型氨基酸转运蛋白1抑制。（Cancer Sci 2009）。
Most tumor cell membranes overexpress l-type amino acid transporter 1, while normal cell membranes contain l-type amino acid transporter 2; both are Na+-independent amino acid transporters. Therefore, compounds that selectively inhibit l-type amino acid transporter 1 offer researchers with a novel cancer molecular target. Synthetic chemistry efforts and in vitro screening have produced a variety of novel compounds possessing high in vitrol-type amino acid transporter 1 selectivity; KYT-0353 was one such compound. The present studies illustrate that KYT-0353 inhibited 14C-leucine uptake and cell growth in human colon cancer-derived HT-29 cells; IC(50)s were 0.06 mu m and 4.1 mu m, respectively. KYT-0353 also inhibited 14C-leucine uptake in mouse renal proximal tubule cells expressing l-type amino acid transporter 1, and inhibited cell growth; IC(50)s were 0.14 mu m and 16.4 mu m, respectively. Compared to control animals, intravenously administered KYT-0353 (12.5 mg/kg and 25.0 mg/kg) showed statistically significant growth inhibition against HT-29 tumors transplanted to nude mice with maximal inhibition ratios of 65.9% and 77.2%, respectively. Body weight increase with time - a safety indicator - was slightly depressed at 12.5 mg/kg and 25.0 mg/kg with maximal ratios of 3.7% (day 2) and 6.3% (day 11), respectively. Thus, KYT-0353 showed significant growth inhibitory effects on HT-29 cells both in vitro and in vivo, whereas it only caused a slight body weight depression. Therefore, KYT-0353 appears to have potential as a novel anti-tumor agent, presumably via selective in vivol-type amino acid transporter 1 inhibition. (Cancer Sci 2009).