Division of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.
Human High Performance and Health Promotion Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.
Int J Mol Sci. 2020 Mar 20;21(6):2132. doi: 10.3390/ijms21062132.
l-type amino acid transporter 1 (LAT1) is an amino acid transporter that is overexpressed in several types of cancer and, thus, it can be a potential target for chemotherapy. The objectives of this study were to (a) synthesize LAT1-targeted chlorambucil derivatives and (b) evaluate their LAT1-mediated cellular uptake as well as antiproliferative activity in vitro in the human breast cancer MCF-7 cell line. Chlorambucil was conjugated to l-tyrosine-an endogenous LAT1 substrate-via either ester or amide linkage (compounds and , respectively). While chlorambucil itself did not bind to LAT1, its derivatives and bound to LAT1 with a similar affinity as with l-tyrosine and their respective cellular uptake was significantly higher than that of chlorambucil in MCF-7. The results of our cellular uptake study are indicative of antiproliferative activity, as a higher intracellular uptake of chlorambucil derivatives resulted in greater cytotoxicity than chlorambucil by itself. LAT1 thus contributes to intracellular uptake of chlorambucil derivatives and, therefore, increases antiproliferative activity. The understanding gained from our research can be used in the development of LAT1-targeted anticancer drugs and prodrugs for site-selective and enhanced chemotherapeutic activity.
L 型氨基酸转运蛋白 1（LAT1）是一种在多种癌症中过度表达的氨基酸转运蛋白，因此它可能成为化疗的潜在靶点。本研究的目的是：（a）合成 LAT1 靶向的苯丁酸氮芥衍生物；（b）评估它们在体外人乳腺癌 MCF-7 细胞系中的 LAT1 介导的细胞摄取和抗增殖活性。通过酯或酰胺键将苯丁酸氮芥与内源性 LAT1 底物 l-酪氨酸偶联（化合物 和 ）。苯丁酸氮芥本身不与 LAT1 结合，但它的衍生物 和 与 LAT1 的结合亲和力与 l-酪氨酸相似，其各自的细胞摄取率明显高于苯丁酸氮芥在 MCF-7 中的摄取率。我们的细胞摄取研究结果表明具有抗增殖活性，因为 LAT1 衍生物的更高细胞内摄取导致比苯丁酸氮芥本身更高的细胞毒性。因此，LAT1 有助于苯丁酸氮芥衍生物的细胞内摄取，从而提高了抗增殖活性。我们的研究成果可用于开发 LAT1 靶向的抗癌药物和前药，以实现位点选择性和增强的化疗活性。
