Background/Objectives:The incidence of head and neck squamous cell carcinoma (HNSCC), currently ~800,000 cases per year worldwide, is rising. Radiotherapy remains a mainstay for the treatment of HNSCC, although inherent radioresistance, particularly in human papillomavirus (HPV)-negative disease subtypes, remains a significant barrier to effective treatment. Therefore, combinatorial strategies using drugs or inhibitors against specific cellular targets are necessary to enhance HNSCC radiosensitivity to lead to an improvement in patient outcomes. Given that radiotherapy acts through targeting and damaging DNA, a common strategy is to focus on enzymes within DNA-dependent cellular pathways, such as DNA damage repair.Methods:Here, we have employed a 3D spheroid model of HNSCC (FaDu) in combination with a targeted drug screen to identify novel radiosensitisers that suppress tumour growth.Results:We identified that histone deacetylases (HDACs) were prominent candidates, and subsequently identified that the HDAC inhibitors mocetinostat and pracinostat, as well as the combined HDAC–epidermal growth factor receptor inhibitor CUDC-101, were effective at radiosensitising cell models of HNSCC (FaDu, A253, UMSCC11b) through their impact on both spheroid growth and clonogenic survival assays. We also demonstrated that this combinatorial strategy leads to inhibition of the repair of DNA double-strand breaks through the neutral comet assay and γH2AX foci analysis using immunofluorescence microscopy, providing a mechanism of action through which HDAC inhibition functions in HNSCC radiosensitisation.Conclusions:We believe that this approach should be further investigated in preclinical models, in order to realise the full therapeutic potential of HDAC inhibition for the radiosensitisation of HNSCC, eventually leading to improved patient treatment efficacy and outcomes.
背景/目的：头颈部鳞状细胞癌（HNSCC）的发病率目前在全球范围内约为每年80万例，且呈上升趋势。放射治疗仍是HNSCC的主要治疗手段，但其固有的放射抵抗性，尤其是在人乳头瘤病毒（HPV）阴性亚型中，仍然是有效治疗的重要障碍。因此，有必要采用针对特定细胞靶点的药物或抑制剂的联合策略，以增强HNSCC的放射敏感性，从而改善患者预后。鉴于放射治疗通过靶向和损伤DNA发挥作用，一个常见的策略是聚焦于DNA依赖性细胞通路中的酶，例如DNA损伤修复相关酶。 方法：本研究采用HNSCC（FaDu细胞）的3D球体模型，结合靶向药物筛选，以识别能够抑制肿瘤生长的新型放射增敏剂。 结果：我们发现组蛋白去乙酰化酶（HDACs）是重要的候选靶点，并进一步证实HDAC抑制剂莫西司他（mocetinostat）和普拉西司他（pracinostat），以及HDAC-表皮生长因子受体联合抑制剂CUDC-101，通过影响球体生长和克隆形成存活实验，能有效增强HNSCC细胞模型（FaDu、A253、UMSCC11b）的放射敏感性。我们还通过中性彗星实验和免疫荧光显微镜下的γH2AX灶点分析证明，该联合策略可抑制DNA双链断裂的修复，从而阐明了HDAC抑制在HNSCC放射增敏中的作用机制。 结论：我们认为，应在临床前模型中进一步研究此方法，以充分挖掘HDAC抑制在HNSCC放射增敏中的治疗潜力，最终提高患者的治疗效果和预后。
肿瘤(癌症)患者之家