Extracellular Release of HMGB1 as an Early Potential Biomarker for the Therapeutic Response in a Xenograft Model of Boron Neutron Capture Therapy

SIMPLE SUMMARY: Boron neutron capture therapy (BNCT) is a non-invasive therapeutic technique for treating malignant tumors, however, there is a lack of methods to evaluate its therapeutic efficacy. Herein, we investigated whether high mobility group box 1 (HMGB1) is a potential biomarker of BNCT response in tumor cells and mice in combination with (10)B-p-boronophenylalanine in the Kyoto University Nuclear Reactor. We observed an increased extracellular HMGB1 release in cancer cells 24 h post-BNCT irradiation, compared to that observed with an equivalent dose of gamma-ray irradiation. High levels of plasma HMGB1 were observed on day 3 post-BNCT irradiation in a xenograft mouse model. These levels were stably detected even when the size of the tumor decreased, suggesting that HMGB1 is a potential biomarker for the therapeutic efficacy of BNCT. ABSTRACT: Boron neutron capture therapy (BNCT) is a non-invasive therapeutic technique for treating malignant tumors, however, methods to evaluate its therapeutic efficacy and adverse reactions are lacking. High mobility group box 1 (HMGB1) is an inflammatory molecule released during cell death. Therefore, we aimed to investigate HMGB1 as a biomarker for BNCT response, by examining the early responses of tumor cells to (10)B-boronophenylalanine (BPA)-based BNCT in the Kyoto University Nuclear Reactor. Extracellular HMGB1 release was significantly increased in human squamous carcinoma SAS and melanoma A375 cells 24 h after neutron irradiation but not after γ-irradiation. At 3 days post-BPA-based BNCT irradiation in a SAS xenograft mouse model, plasma HMGB1 levels were higher than those in the non-irradiation control, and HMGB1 was detected in both nuclei and cytoplasm in tumor cells. Additionally, increased plasma HMGB1 levels post-BNCT irradiation were detected even when tumors decreased in size. Collectively, these results indicate that the extracellular HMGB1 release occurs at an early stage and is persistent when tumors are reduced in size; therefore, it is a potential biomarker for evaluating the therapeutic response during BNCT.