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: Printip Wongthai, Kohei Hagiwara, Yurika Miyoshi, Pattama Wiriyasermkul, Ling Wei, Ryuichi Ohgaki, Itsuro Kato, Kenji Hamase, Shushi Nagamori, Yoshikatsu Kanai
• Journal: Cancer science (Cancer Sci) Vol. 106 Issue 3 Pg. 279-86 (Mar 2015) ISSN: 1349-7006 [Electronic] England
• PMID: 25580517 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Chemical References

• Amino Acid Transport System y+
• Amino Acid Transport System y+L
• Amino Acid Transport Systems
• Boron Compounds
• Fusion Regulatory Protein 1, Light Chains
• Neurotransmitter Transport Proteins
• RNA, Small Interfering
• SLC7A8 protein, mouse
• Slc6a14 protein, rat
• Slc7a7 protein, mouse
• Phenylalanine
• Boron
• 4-boronophenylalanine

Topics

• Amino Acid Transport System y+ (metabolism)
• Amino Acid Transport System y+L
• Amino Acid Transport Systems (metabolism)
• Animals
• Biological Transport
• Boron (metabolism)
• Boron Compounds (metabolism)
• Boron Neutron Capture Therapy
• Cell Line, Tumor
• Fusion Regulatory Protein 1, Light Chains (metabolism)
• HeLa Cells
• Humans
• MCF-7 Cells
• Neurotransmitter Transport Proteins (metabolism)
• Oocytes (metabolism)
• Phenylalanine (analogs & derivatives, metabolism)
• RNA Interference
• RNA, Small Interfering
• Xenopus