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Tyrosine–Chlorambucil Conjugates Facilitate Cellular Uptake through L-Type Amino Acid Transporter 1 (LAT1) in Human Breast Cancer Cell Line MCF-7

机译:酪氨酸 - 氯蛋白缀合物促进通过L型氨基酸转运蛋白1(LAT1)在人乳腺癌细胞系MCF-7中的细胞摄取

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摘要

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 1 and 2, respectively). While chlorambucil itself did not bind to LAT1, its derivatives 1 and 2 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.
机译:L型氨基酸转运蛋白1(LAT1)是氨基酸转运蛋白,其在几种类型的癌症中过表达,因此,它可以是化疗的潜在目标。本研究的目的是(a)合成Lat1靶向氯胺衍生物和(b)评估其LAT1介导的细胞摄取以及人乳腺癌MCF-7细胞体外体外抗增殖活性。通过酯或酰胺键(分别分别为酰胺键(分别化合物1和2)与L-酪氨酸 - 一种内源LAT1基底缀合物。虽然氯镁本身未与Lat1结合,但其与与L-酪氨酸相似的亲和力与LAT1结合的衍生物1和2的衍生物1和2明显高于MCF-7中的氯镁胺的亲和力。我们的蜂窝摄取研究的结果表明抗增殖活性,因为氯镁衍生物的较高细胞内摄取导致具有更大的细胞毒性而不是氯苯胺。因此,LAT1有助于细胞内吸收氯镁衍生物,因此增加抗增殖活性。我们的研究中获得的理解可用于抗LAT1针对性抗癌药物和前药的发展,用于出位选择性和增强的化学治疗活动。

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