Laboratory of Bioanalysis, Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University of Lodz, ul. Muszyńskiego 1, Lodz, 90-151, Poland.
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, Kuopio, 70211, Finland.
Apoptosis. 2020 Jun;25(5-6):426-440. doi: 10.1007/s10495-020-01603-7.
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.
氨基酸含量的增加对于癌细胞的持续生长和存活是必不可少的。因此，已经开发了氨基酸转运体的抑制剂，例如 L 型氨基酸转运体 1（LAT1）。在这项研究中，研究了先前报道的 LAT1 抑制剂（KMH-233）对人脐静脉内皮细胞（HUVEC）和人主动脉平滑肌细胞（AoSMC）的血液相容性和毒性。此外，评估了其对人乳腺癌腺癌细胞（MCF-7）的细胞毒性作用及其影响哺乳动物（或机制）靶标雷帕霉素（mTOR）和核因子 kappa-轻链增强子的能力激活 B 细胞（NF-κB）信号。此外，在小鼠中腹腔内（i.p.）给予 LAT1 抑制剂（23 μmol/kg）后，评估了该抑制剂对细胞表面 LAT1 功能的调节作用以及脑氨基酸动态平衡的影响。结果表明，LAT1 抑制剂（KMH-233）在低于 25 μM 的浓度下是血液相容的，并且不会影响血浆中的凝血。然而，它可以减少 mTOR 和 NF-κB 的总蛋白量，导致 LAT1 表达的癌细胞凋亡增加。最重要的是，抑制剂不会影响小鼠脑中 L-Leu、L-Tyr 或 L-Trp 的水平，也不会调节 MCF-7 细胞表面上 LAT1 的功能。因此，该抑制剂可以被认为是一种安全但有效的抗癌药物。然而，由于癌细胞对增加的氨基酸需求的代偿机制，当与其他化疗药物（如蛋白酶抑制剂贝替司汀）联合使用时，该化合物在诱导细胞凋亡方面最为有效，如本研究所示。
Zotero 插件
