Development of Sesamol Carbamate-L-Phenylalanine Prodrug Targeting L-Type Amino Acid Transporter1 (LAT1) as a Potential Antiproliferative Agent against Melanoma
| Autor: | Tarapong Srisongkram, Katayun Bahrami, Juulia Järvinen, Juri Timonen, Jarkko Rautio, Natthida Weerapreeyakul |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | International Journal of Molecular Sciences, Vol 23, Iss 15, p 8446 (2022) |
| Druh dokumentu: | article |
| ISSN: | 1422-0067 1661-6596 |
| DOI: | 10.3390/ijms23158446 |
| Popis: | Sesamol is a compound reported to have anti-melanogenesis and anti-melanoma actions. Sesamol, however, has low intracellular drug concentration and fast excretion, which can limit its benefits in the clinic. To overcome this drawback and increase intracellular delivery of sesamol into the target melanoma, research has focused on L-type amino acid transporter 1 (LAT1)-mediated prodrug delivery into melanoma cells. The sesamol prodrug was designed by conjugating sesamol with L-phenylalanine at the para position with a carbamate bond. LAT1 targeting was evaluated vis-à-vis a competitive [14C]-leucine uptake inhibition. The sesamol prodrug has a higher [14C]-leucine uptake inhibition than sesamol in human LAT1-transfected HEK293 cells. Moreover, the sesamol prodrug was taken up by LAT1-mediated transport into SK-MEL-2 cells more effectively than sesamol. The sesamol prodrug underwent complete hydrolysis, releasing the active sesamol at 72 h, which significantly exerted its cytotoxicity (IC50 of 29.3 µM) against SK-MEL-cells more than sesamol alone. Taken together, the strategy for LAT1-mediated prodrug delivery has utility for the selective uptake of sesamol, thereby increasing its intracellular concentration and antiproliferation activity, targeting melanoma SK-MEL-2 cells that overexpress the LAT1 protein. The sesamol prodrug thus warrants further evaluation in an in vivo model. |
| Databáze: | Directory of Open Access Journals |
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