title: Boronophenylalanine, a boron delivery agent for boron neutron capture therapy, is transported by ATB0,+, LAT1 and LAT2.
abstract: The efficacy of boron neutron capture therapy relies on the selective delivery of boron carriers to malignant cells. p-Boronophenylalanine (BPA), a boron delivery agent, has been proposed to be localized to cells through transporter-mediated mechanisms. In this study, we screened aromatic amino acid transporters to identify BPA transporters. Human aromatic amino acid transporters were functionally expressed in Xenopus oocytes and examined for BPA uptake and kinetic parameters. The roles of the transporters in BPA uptake were characterized in cancer cell lines. For the quantitative assessment of BPA uptake, HPLC was used throughout the study. Among aromatic amino acid transporters, ATB(0,+), LAT1 and LAT2 were found to transport BPA with Km values of 137.4 ± 11.7, 20.3 ± 0.8 and 88.3 ± 5.6 μM, respectively. Uptake experiments in cancer cell lines revealed that the LAT1 protein amount was the major determinant of BPA uptake at 100 μM, whereas the contribution of ATB(0,+) became significant at 1000 μM, accounting for 20-25% of the total BPA uptake in MCF-7 breast cancer cells. ATB(0,+), LAT1 and LAT2 transport BPA at affinities comparable with their endogenous substrates, suggesting that they could mediate effective BPA uptake in vivo. The high and low affinities of LAT1 and ATB(0,+), respectively, differentiate their roles in BPA uptake. ATB(0,+), as well as LAT1, could contribute significantly to the tumor accumulation of BPA at clinical dose.
authors.affiliation: Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Printip
authors.initials: P
authors.lastname: Wongthai
authors.forename: Kohei
authors.initials: K
authors.lastname: Hagiwara
authors.forename: Yurika
authors.initials: Y
authors.lastname: Miyoshi
authors.forename: Pattama
authors.initials: P
authors.lastname: Wiriyasermkul
authors.forename: Ling
authors.initials: L
authors.lastname: Wei
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Ohgaki
authors.forename: Itsuro
authors.initials: I
authors.lastname: Kato
authors.forename: Kenji
authors.initials: K
authors.lastname: Hamase
authors.forename: Shushi
authors.initials: S
authors.lastname: Nagamori
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D027241:Amino Acid Transport System y+L; D026905:Amino Acid Transport Systems / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001895:Boron / Q000378:metabolism; D001896:Boron Compounds / Q000378:metabolism*; D016754:Boron Neutron Capture Therapy; D045744:Cell Line, Tumor; D027301:Fusion Regulatory Protein 1, Light Chains / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D050479:Neurotransmitter Transport Proteins / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D014981:Xenopus
chemical_list: D027182:Amino Acid Transport System y+; D027241:Amino Acid Transport System y+L; D026905:Amino Acid Transport Systems; D001896:Boron Compounds; D027301:Fusion Regulatory Protein 1, Light Chains; D050479:Neurotransmitter Transport Proteins; D034741:RNA, Small Interfering; C518286:SLC7A8 protein, mouse; C515774:Slc6a14 protein, rat; C518287:Slc7a7 protein, mouse; D010649:Phenylalanine; D001895:Boron; C033685:4-boronophenylalanine
keywords: Amino acid transporter; BNCT; BPA; cancer cell lines; drug delivery