Increased amounts of amino acids are essential for cancer cells to support their sustained growth and survival. Therefore, inhibitors of amino acid transporters, such as L-type amino acid transporter 1 (LAT1) have been developed. In this study, a previously reported LAT1-inhibitor (KMH-233) was studied for its hemocompatibility and toxicity towards human umbilical vein endothelial cells (HUVEC) and human aortic smooth muscle cells (AoSMCs). Furthermore, the cytotoxic effects against human breast adenocarcinoma cells (MCF-7) and its ability to affect mammalian (or mechanistic) target of rapamycin (mTOR) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling were evaluated. Moreover, the effects of this inhibitor to modulate LAT1 function on the cell surface and the brain amino acid homeostasis were evaluated after intraperitoneal (i.p.) administration of LAT1-inhibitor (23 µmol/kg) in mice. The results showed that LAT1-inhibitor (KMH-233) is hemocompatible at concentrations below 25 µM and it does not affect coagulation in plasma. However, it can reduce the total protein amount of mTOR and NF-κB, resulting in increased apoptosis in LAT1-expressing cancer cells. Most importantly, the inhibitor did not affect mouse brain levels of L-Leu, L-Tyr or L-Trp or modulate the function of LAT1 on the MCF-7 cell surface. Therefore, this inhibitor can be considered as a safe but effective anti-cancer agent. However, due to the compensative mechanism of cancer cells for their increased amino acid demand, this compound is most effective inducing apoptosis when used in combinations with other chemotherapeutics, such as protease inhibitor, bestatin, as demonstrated in this study.

中文翻译：

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血液相容性LAT1抑制剂可诱导癌细胞凋亡，而不会影响脑氨基酸稳态。

氨基酸的增加对于癌细胞支持其持续生长和存活至关重要。因此，已经开发了氨基酸转运蛋白的抑制剂，例如L型氨基酸转运蛋白1（LAT1）。在这项研究中，对先前报道的LAT1抑制剂（KMH-233）的血液相容性和对人脐静脉内皮细胞（HUVEC）和人主动脉平滑肌细胞（AoSMCs）的毒性进行了研究。此外，对人乳腺癌细胞（MCF-7）的细胞毒性作用及其影响雷帕霉素（mTOR）和激活的B细胞核因子κ轻链增强剂（NF-κB）的哺乳动物（或机制）靶标的能力评估信号。此外，在小鼠腹腔内（ip）施用LAT1抑制剂（23 µmol / kg）后，评估了该抑制剂调节LAT1在细胞表面和大脑氨基酸稳态中的作用。结果表明，LAT1抑制剂（KMH-233）在低于25 µM的浓度下具有血液相容性，并且不影响血浆中的凝血。但是，它可以减少mTOR和NF-κB的总蛋白量，从而导致表达LAT1的癌细胞凋亡增加。最重要的是，该抑制剂不会影响小鼠大脑中L-Leu，L-Tyr或L-Trp的水平，也不会影响MCF-7细胞表面LAT1的功能。因此，该抑制剂可以被认为是安全而有效的抗癌剂。但是，由于癌细胞对氨基酸需求增加的补偿机制，