Structural properties for selective and efficient l-type amino acid transporter 1 (LAT1) mediated cellular uptake

Kärkkäinen, Jussi M.; Gynther, Mikko; Kokkola, Tarja; Petsalo, Aleksanteri; Auriola, Seppo; Lahtela‐Kakkonen, Maija; Laine, Krista; Rautio, Jarkko; Huttunen, Kristiina M.

doi:10.1016/j.ijpharm.2018.04.025

Cited by 22 publications

(22 citation statements)

References 50 publications

(71 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, no direct conclusion of the relation between lipophilicity and LAT1 affinity can be drawn. Lastly, compounds having unfavorable structures, such as attaching the parent drug (ketoprofen) to the para -position of the aromatic ring of amino acid residue (compound 3 ) resulted in lower affinity and higher IC 50 values, as expected according to the literature [ 16 , 17 , 34 , 35 ].…”

Section: Resultssupporting

confidence: 60%

Comparison of Experimental Strategies to Study l-Type Amino Acid Transporter 1 (LAT1) Utilization by Ligands

et al. 2021

Self Cite

View full text Add to dashboard Cite

l-Type amino acid transporter 1 (LAT1), expressed abundantly in the brain and placenta and overexpressed in several cancer cell types, has gained a lot of interest in drug research and development, as it can be utilized for brain-targeted drug delivery, as well as inhibiting the essential amino acid supply to cancer cells. The structure of LAT1 is today very well-known and the interactions of ligands at the binding site of LAT1 can be modeled and explained. However, less is known of LAT1′s life cycle within the cells. Moreover, the functionality of LAT1 can be measured by several different methods, which may vary between the laboratories and make the comparison of the results challenging. In the present study, the usefulness of indirect cis-inhibition methods and direct cellular uptake methods and their variations to interpret the interactions of LAT1-ligands were evaluated. Moreover, this study also highlights the importance of understanding the intracellular kinetics of LAT1-ligands, and how they can affect the regular function of LAT1 in critical tissues, such as the brain. Hence, it is discussed herein how the selected methodology influences the outcome and created knowledge of LAT1-utilizing compounds.

show abstract

Section: Resultssupporting

confidence: 60%

Comparison of Experimental Strategies to Study l-Type Amino Acid Transporter 1 (LAT1) Utilization by Ligands

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition, the binding affinity to LAT1 could also be enhanced by structural modifications. The meta-conjugation of l-phenylalanine (or l-tyrosine) to a parent drug has been shown to display higher binding affinity to LAT1 than para-conjugation [2,26]. In our experiment, chlorambucil conjugation to l-tyrosine derivatives at the meta-position was highly acid sensitive, and both the ester and amide bonds were cleaved during the deprotection process (unpublished data).…”

Section: Discussionmentioning

confidence: 51%

“…Nonetheless, the high-binding affinity is not obligatory to the efficient LAT1-mediated cellular uptake [25]. Smaller compounds seem to be taken up by LAT1 faster than the larger ones, at the expense of specificity and affinity [26]. By contrast, the larger molecules with high lipophilicity can bind more efficiently to LAT1, at the expense of transport capacity, resulting in compounds acting as inhibitors rather than substrates [27].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Pocasap

Weerapreeyakul

Timonen

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…LAT1 belongs to the L-type amino acid transporter (LAT) family [28] with broad structural requirements vis-à-vis LAT1 substrates. The shared common functional groups for LAT1 substrates are amino groups and hydrophilic meta-substituted aromatic rings (or hydrophobic side chains) [28,29,30,31,32]. Both the amino and carboxylic acid functional groups are mooted to be essential for transporter recognition [33], but some carboxylic esters [29] or carbonyl oxygens and alkoxy oxygens [31] could be taken up via LAT1 [29], indicating that the carboxyl functional group may not be essential [30,31,32].…”

Section: Discussionmentioning

confidence: 99%

Role of L-Type Amino Acid Transporter 1 (LAT1) for the Selective Cytotoxicity of Sesamol in Human Melanoma Cells

et al. 2019

Self Cite

View full text Add to dashboard Cite

Sesamol is effective against melanoma cells with less damage to normal cells. The underlying selective cytotoxicity of sesamol in melanoma vs. non-cancerous cells is undefined. Melanoma cells differ from normal cells by over-expression of the L-type amino acid transporter 1 (LAT1). We sought to clarify the transport mechanism on selective cytotoxicity of sesamol in melanoma cells. A human melanoma cell line (SK-MEL-2) and African monkey epithelial cell line (Vero) were used to study the cellular uptake and cytotoxicity of sesamol. The intracellular concentration of sesamol was quantified by UV-HPLC. The cytotoxicity was determined by neutral red uptake assay. Sesamol showed a higher distribution volume and uptake clearance in SK-MEL-2 than Vero cells. Sesamol was distributed by both carrier-mediated and passive transport by having greater carrier-mediated transport into SK-MEL-2 cells than Vero cells. Higher mRNA expression and function of LAT1 over LAT2 were evident in SK-MEL-2 cells compared to Vero cells. Sesamol uptake and sesamol cytotoxicity were inhibited by the LAT1 inhibitor, suggesting LAT1 had a role in sesamol transport and its bioactivity in melanoma. The LAT1-mediated transport of sesamol is indicative of how it engages cytotoxicity in melanoma cells with promising therapeutic benefits.

show abstract

Structural properties for selective and efficient l-type amino acid transporter 1 (LAT1) mediated cellular uptake

Cited by 22 publications

References 50 publications

Comparison of Experimental Strategies to Study l-Type Amino Acid Transporter 1 (LAT1) Utilization by Ligands

Comparison of Experimental Strategies to Study l-Type Amino Acid Transporter 1 (LAT1) Utilization by Ligands

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

Role of L-Type Amino Acid Transporter 1 (LAT1) for the Selective Cytotoxicity of Sesamol in Human Melanoma Cells

Contact Info

Product

Resources

About