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The uptake of boron into tumor cells is a key factor in the biological effects of boron neutron capture therapy (BNCT). The uptake of boron agents is suppressed in hypoxic conditions, but the mechanism of hypoxia-induced modulation of suppression of boron uptake is not clear. Therefore, we evaluated whether hypoxia-inducible factor 1α (HIF-1α) contributes to attenuation of the antitumor effects of BNCT in hypoxic tumor cells. We also tested whether YC-1, a HIF-1α-targeting inhibitor, has therapeutic potential with BNCT. To elucidate the mechanism of attenuation of the effects of BNCT caused by hypoxia, deferoxamine (DFO) was used in experiments. Cells were incubated in normal oxygen, hypoxic conditions (1% O2) or 5 μM DFO for 24 h. Then, cells were treated with 10B-boronophenylalanine (BPA) for 2 h and boron accumulation in cells was evaluated. To clarify the relationship between HIF-1α and L-type amino acid transporter 1 (LAT1), gene expression was evaluated by a using HIF-1α gene knockdown technique. Finally, to improve attenuation of the effects of BNCT in hypoxic cells, BNCT was combined with YC-1. Boron uptake was continuously suppressed up to 2 h after administration of BPA by 5 μM DFO treatment. In cells treated with 5 μM DFO, LAT1 expression was restored in HIF-1α-knocked down samples in all cell lines, revealing that HIF-1α suppresses LAT1 expression in hypoxic cells. From the results of the surviving fraction after BNCT combined with YC-1, treatment with YC-1 sensitized the antitumor effects of BNCT in cells cultured in hypoxia.

YC-1 sensitizes the antitumor effects of boron neutron capture therapy in hypoxic tumor cells