Intracellular uptake and inhibitory activity of aromatic fluorinated amino acids in human breast cancer cells

Abstract

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 IC(50) values in the low micromolar range (3-15 microM). Additionally, using L-4-[14C]fluorotryptophan, and L-6-[14C]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.

Performance Analysis of Orthogonal Pairs Designed for an Expanded Eukaryotic Genetic Code

“…Indeed, Wang and co-workers observed roughly 9 mM intracellular dansylalanine upon esterification of the amino acid [62]. Giese et al recently demonstrated that fluorinated tryptophan is actively taken up into mammalian cells to an intracellular concentration exceeding the extracelluar by 70-fold [63]. A comparable accumulation could elevate the intracellular Bpa concentration above 5 mM when the cells are supplemented with 1 mM in the medium, as in our experiments.…”

Transfer RNA Misidentification Scrambles Sense Codon Recoding

“…Thus, future work is needed to develop PylRS variants that will efficiently acylate Mycoplasma cell-permeable ncAAs, under conditions that lead to high levels of these AAs in the cell. [26] Engineering AARS variants with high catalytic efficiencies for ncAAs is particularly important, because many currently available orthogonal pairs are inefficient compared with natural AARSs. [27] …”

A mixture of amino acids and other small molecules present in the serum suppresses the growth of murine and human tumors in vivo

“…Since the elevated uptake of glucose and increased glycolitic activity of cancer cells has been first reported by Otto Warburg,9 it has been shown that in addition to glucose many molecules (amino acids, vitamins) are accumulated in cancer cells 10–12. The accumulation of these substances by cancer cells is utilized in positron emission tomography,13 and targeting strategies has been started to emerge on the basis of amino acid and vitamin accumulation 14, 15. In recent years it became increasingly clear that there are a significant number of common signaling pathways regulating both cellular metabolism and cell proliferation 16.…”