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Fujimura, Atsushi Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences ORCID Kaken ID researchmap
Yasui, Seiji Neutron Therapy Research Center, Okayama University
Igawa, Kazuyo Neutron Therapy Research Center, Okayama University
Ueda, Ai Neutron Therapy Research Center, Okayama University
Watanabe, Kaori Neutron Therapy Research Center, Okayama University
Hanafusa, Tadashi Neutron Therapy Research Center, Okayama University ORCID Kaken ID publons researchmap
Ichikawa, Yasuaki Neutron Therapy Research Center, Okayama University
Yoshihashi, Sachiko Graduate School of Engineering, Nagoya University
Tsuchida, Kazuki Graduate School of Engineering, Nagoya University
Kamiya, Atsunori Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Furuya, Shuichi Neutron Therapy Research Center, Okayama University
Abstract
Boron neutron capture therapy (BNCT) requires pharmaceutical innovations and molecular-based evidence of effectiveness to become a standard cancer therapeutic in the future. Recently, in Japan, 4-borono-L-phenylalanine (BPA) was approved as a boron agent for BNCT against head and neck (H&N) cancers. H&N cancer appears to be a suitable target for BPA-BNCT, because the expression levels of L-type amino acid transporter 1 (LAT1), one of the amino acid transporters responsible for BPA uptake, are elevated in most cases of H&N cancer. However, in other types of cancer including malignant brain tumors, LAT1 is not always highly expressed. To expand the possibility of BNCT for these cases, we previously developed poly-arginine peptide (polyR)-conjugated mercaptoundecahydrododecaborate (BSH). PolyR confers the cell membrane permeability and tumor selectivity of BSH. However, the molecular determinants for the properties are not fully understood. In this present study, we have identified the cluster of differentiation 44 (CD44) protein and translational machinery proteins as a major cell surface target and intracellular targets of BSH-polyR, respectively. CD44, also known as a stem cell-associated maker in various types of cancer, is required for the cellular uptake of polyR-conjugated molecules. We showed that BSH-polyR was predominantly delivered to a CD44(High) cell population of cancer cells. Once delivered, BSH-polyR interacted with the translational machinery components, including the initiation factors, termination factors, and poly(A)-biding protein (PABP). As a proof of principle, we performed BSH-polyR-based BNCT against glioma stem-like cells and revealed that BSH-polyR successfully induced BNCT-dependent cell death specifically in CD44(High) cells. Bioinformatics analysis indicated that BSH-polyR would be suitable for certain types of malignant tumors. Our results shed light on the biochemical properties of BSH-polyR, which may further contribute to the therapeutic optimization of BSH-BNCT in the future.
Keywords
boron neutron capture therapy (BNCT)
BSH-polyR
CD44
translational machinery
bioinformatics
Published Date
2020-09-23
Publication Title
Cells
Volume
volume9
Issue
issue10
Publisher
MDPI
Start Page
2149
ISSN
2073-4409
Content Type
Journal Article
language
英語
OAI-PMH Set
岡山大学
Copyright Holders
© 2020 by the authors.
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DOI
Web of Science KeyUT
Related Url
isVersionOf https://doi.org/10.3390/cells9102149
License
http://creativecommons.org/licenses/by/4.0/
Funder Name
Japan Agency for Medical Research and Development
助成番号
18072932