Department of Radiation Oncology, Samsung Medical Center, Seoul 06351, Korea.
School of Medicine, Sungkyunkwan University, Seoul 06351, Korea.
Cells. 2021 Mar 4;10(3):554. doi: 10.3390/cells10030554.
Epigenetic modulation by histone deacetylase (HDAC) inhibitors is an attractive anti-cancer strategy for diverse hematological and solid cancers. Herein, we explored the relative effectiveness of the pan-HDAC inhibitor panobinostat in combination with proton over X-ray irradiation in HCC cells. Clonogenic survival assays revealed that radiosensitization of Huh7 and Hep3B cells by panobinostat was more evident when combined with protons than X-rays. Panobinostat increased G2/M arrest and production of intracellular reactive oxygen species, which was further enhanced by proton irradiation. Immunofluorescence staining of γH2AX showed that panobinostat enhanced proton-induced DNA damage. Panobinostat dose-dependently decreased expression of an anti-apoptotic protein, Mcl-1, concomitant with increasing acetylation of histone H4. The combination of panobinostat with proton irradiation enhanced apoptotic cell death to a greater extent than that with X-ray irradiation. Depletion of Mcl-1 by RNA interference enhanced proton-induced apoptosis and proton radiosensitization, suggesting a potential role of Mcl-1 in determining proton sensitivity. Together, our findings suggest that panobinostat may be a promising combination agent for proton beam therapy in HCC treatment.
组蛋白去乙酰化酶（HDAC）抑制剂的表观遗传调节是一种有吸引力的抗癌策略，适用于多种血液系统和实体肿瘤。在此，我们研究了泛 HDAC 抑制剂帕比司他与质子相对于 X 射线辐照联合在 HCC 细胞中的相对有效性。集落形成存活实验显示，与 X 射线相比，帕比司他与质子联合辐照更能增强 Huh7 和 Hep3B 细胞的放射敏感性。帕比司他增加了 G2/M 期阻滞和细胞内活性氧的产生，质子照射进一步增强了这一作用。γH2AX 的免疫荧光染色显示，帕比司他增强了质子诱导的 DNA 损伤。帕比司他剂量依赖性地下调了抗凋亡蛋白 Mcl-1 的表达，同时增加了组蛋白 H4 的乙酰化。与 X 射线相比，帕比司他与质子照射联合增强了细胞凋亡死亡的程度。RNA 干扰耗竭 Mcl-1 增强了质子诱导的凋亡和质子放射增敏作用，表明 Mcl-1 在决定质子敏感性方面可能发挥作用。总之，我们的研究结果表明，帕比司他可能是 HCC 质子束治疗的一种有前途的联合治疗药物。
