Intracellular uptake and inhibitory activity of aromatic fluorinated amino acids in human breast cancer cells
Intracellular uptake and inhibitory activity of aromatic fluorinated amino acids in human breast cancer cells
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DOI：
10.1002/cmdc.200800108
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发表时间：
2008-09-01
期刊：
影响因子：
3.4
通讯作者：
Lilie, Hauke
中科院分区：
文献类型：
--
作者：
Giese, Christoph;Lepthien, Sandra;Lilie, Hauke
天然存在或化学合成的非蛋白氨基酸正在成为现代药物发现的重要工具。在此背景下，氟化氨基酸在新型药物和药物的开发中具有巨大的潜力。为了评估苯丙氨酸、酪氨酸和色氨酸的不同氟化芳香族氨基酸类似物是否有可能作为治疗药物，我们检查了它们对人乳腺癌细胞系 MCF-7 生长的细胞抑制和细胞毒性作用。在所有测试的类似物中，L-4-氟色氨酸、L-6-氟色氨酸和L-对氟苯丙氨酸有效且不可逆地抑制细胞生长，IC50值在低微摩尔范围内（3-15μM）。此外，使用L-4-[C-14]氟色氨酸和L-6-[C-14]氟色氨酸，我们发现这些氟化氨基酸的细胞摄取是通过主动转运发生的，细胞内浓度比细胞外浓度高70倍。我们确定系统 L 是负责的氨基酸转运蛋白。我们的研究结果完全支持这样的观点，即氟化芳香族氨基酸类似物是有前途的化疗药物，有可能与经典癌症疗法联合使用，并作为某些肿瘤类型（如黑色素瘤）的新细胞毒性药物。
Nonproteinogenic amino acids that either occur naturally or are synthesized chemically are becoming important tools in modern drug discovery. In this context, fluorinated amino acids have great potential in the development of novel pharmaceuticals and drugs. To assess whether different fluorinated aromatic amino acid analogues of phenylalanine, tyrosine, and tryptophan are potentially interesting as therapeutic drugs, we examined their cytostatic and cytotoxic effects on the growth of the human breast cancer cell line MCF-7. Of all the tested analogues L-4-fluorotryptophan, L-6-fluorotryptophan and L-p-fluorophenylalanine effectively and irreversibly inhibited cell growth with IC50 values in the low micromolar range (3-15 mu M). Additionally, using L-4-[C-14]fluorotryptophan and L-6-[C-14]fluorotryptophan, we discovered that the cellular uptake of these fluorinated amino acids occurs through active transport with a 70-fold excess of intracellular over extracellular concentrations. We identified system L as the responsible amino acid transporter. Our findings fully support the idea that fluorinated aromatic amino acid analogues are promising chemotherapeutics with the potential for use in combination with classical cancer therapy, and as new cytotoxic drugs for certain tumor types such as melanoma.