Lai Zih-Yin, Huang Yu-Hsuan, Zhou Ting-Yu, Lee Chi-Ying, Shiao Yu-Ming, Chen Yi-Wei, Chou Fong-In, Chen Jen-Kun, Chuang Yung-Jen
School of Medicine, National Tsing Hua University, Hsinchu, Taiwan R.O.C.
Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan R.O.C.
Jpn J Radiol. 2025 Aug 18. doi: 10.1007/s11604-025-01852-z.
Hepatocellular carcinoma (HCC), particularly in recurrent or treatment-refractory cases, often exhibits poor responsiveness to radiation therapy, increasing the risk of radiation-induced liver disease, necessitating innovative treatment approaches. Boric acid-mediated boron neutron capture therapy (BA-BNCT) has emerged as a promising approach for liver cancer. This study aims to improve BA-BNCT efficacy for radioresistant HCC by exploring sensitization agents, enhancing treatment while minimizing irradiation doses and side effects.
We targeted the DNA homologous recombination repair (HRR) protein RAD51. Before neutron irradiation, a RAD51 inhibitor, B02, was administered to evaluate its sensitization effect on both HepG2 and the radioresistant HepG2R cells. We examined the cell death mechanism, focusing on the expression profile of LC3B after BA-BNCT, to investigate its impact on DNA repair responses, especially on autophagy and apoptosis.
We observed that inhibition of RAD51 led to increased γH2AX, the DNA double-strand break marker. Additionally, combining the RAD51 inhibitor B02 with BA-BNCT resulted in tumor cell arrest in the G/G phase, indicating altered cell cycle regulation. In exploring cell death mechanisms, we observed increased autophagy following BNCT, potentially as a response to cellular stress induced by DNA damage in tumor cells. The combination of B02 and BA-BNCT significantly disrupted autophagic flux and promoted apoptosis in the tumor cells.
Combining a RAD51 inhibitor with BA-BNCT significantly enhances the anti-tumor efficacy against radioresistant HCC and parental HCC cells. This proof-of-concept study suggests that the combination treatment can achieve comparable or superior therapeutic effects using lower radiation doses, thereby reinforcing the potential of BNCT for treating recurrent HCC.
肝细胞癌（HCC），尤其是复发性或难治性病例，对放射治疗的反应通常较差，增加了放射性肝病的风险，因此需要创新的治疗方法。硼酸介导的硼中子俘获疗法（BA-BNCT）已成为一种有前景的肝癌治疗方法。本研究旨在通过探索增敏剂来提高BA-BNCT对放射抗性HCC的疗效，在减少照射剂量和副作用的同时增强治疗效果。
我们靶向DNA同源重组修复（HRR）蛋白RAD51。在中子照射前，给予RAD51抑制剂B02，以评估其对HepG2和放射抗性HepG2R细胞的增敏作用。我们研究了细胞死亡机制，重点关注BA-BNCT后LC3B的表达谱，以研究其对DNA修复反应的影响，特别是对自噬和凋亡的影响。
我们观察到RAD51的抑制导致DNA双链断裂标志物γH2AX增加。此外，将RAD51抑制剂B02与BA-BNCT联合使用导致肿瘤细胞停滞在G/G期，表明细胞周期调控发生改变。在探索细胞死亡机制时，我们观察到BNCT后自噬增加，这可能是对肿瘤细胞DNA损伤诱导的细胞应激的一种反应。B02和BA-BNCT的联合显著破坏了自噬流并促进了肿瘤细胞的凋亡。
将RAD51抑制剂与BA-BNCT联合使用可显著增强对放射抗性HCC和亲本HCC细胞的抗肿瘤疗效。这项概念验证研究表明，联合治疗可以使用较低的辐射剂量实现相当或更好的治疗效果，从而增强了BNCT治疗复发性HCC的潜力。
