5-Aminolevulinic acid increases boronophenylalanine uptake into glioma stem cells and may sensitize malignant glioma to boron neutron capture therapy

• Published in: Scientific reports Vol. 13; no. 1; p. 10173
• Main Authors: Fukumura, Masao, Nonoguchi, Naosuke, Kawabata, Shinji, Hiramatsu, Ryo, Futamura, Gen, Takeuchi, Koji, Kanemitsu, Takuya, Takata, Takushi, Tanaka, Hiroki, Suzuki, Minoru, Sampetrean, Oltea, Ikeda, Naokado, Kuroiwa, Toshihiko, Saya, Hideyuki, Nakano, Ichiro, Wanibuchi, Masahiko
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.06.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/532; 631/67/1922; Amino acids; Aminolevulinic acid; Aminolevulinic Acid - pharmacology; Animals; Blood levels; Boron; Boron Compounds; Boron Neutron Capture Therapy; Brain Neoplasms - radiotherapy; Glioma; Glioma - radiotherapy; Glioma cells; Humanities and Social Sciences; Humans; Mice; multidisciplinary; Neoplastic Stem Cells; Neutrons; Radiation therapy; Science; Science (multidisciplinary); Stem cells; Tumor cells; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-37296-6

Boron neutron capture therapy (BNCT) is a high-LET particle radiotherapy clinically tested for treating malignant gliomas. Boronophenylalanine (BPA), a boron-containing phenylalanine derivative, is selectively transported into tumor cells by amino acid transporters, making it an ideal agent for BNCT. In this study, we investigated whether the amino acid 5-aminolevulinic acid (ALA) could sensitize glioma stem cells (GSCs) to BNCT by enhancing the uptake of BPA. Using human and mouse GSC lines, pre-incubation with ALA increased the intracellular accumulation of BPA dose-dependent. We also conducted in vivo experiments by intracerebrally implanting HGG13 cells in mice and administering ALA orally 24 h before BPA administration (ALA + BPA-BNCT). The ALA preloading group increased the tumor boron concentration and improved the tumor/blood boron concentration ratio, resulting in improved survival compared to the BPA-BNCT group. Furthermore, we found that the expression of amino acid transporters was upregulated following ALA treatment both in vitro and in vivo, particularly for ATB 0,+ . This suggests that ALA may sensitize GSCs to BNCT by upregulating the expression of amino acid transporters, thereby enhancing the uptake of BPA and improving the effectiveness of BNCT. These findings have important implications for strategies to improve the sensitivity of malignant gliomas to BPA-BNCT.