Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.
Comprehensive Cancer Center Erlangen-Europäische Metropolregion Nürnberg (CCC ER-EMN), 91054 Erlangen, Germany.
Int J Mol Sci. 2024 May 22;25(11):5629. doi: 10.3390/ijms25115629.
(1) Head and neck squamous cell carcinoma (HNSCC) is common, while treatment is difficult, and mortality is high. Kinase inhibitors are promising to enhance the effects of radiotherapy. We compared the effects of the PARP inhibitors talazoparib and niraparib and that of the DNA-PKcs inhibitor AZD7648, combined with ionizing radiation. (2) Seven HNSCC cell lines, including Cal33, CLS-354, Detroit 562, HSC4, RPMI2650 (HPV-negative), UD-SCC-2 and UM-SCC-47 (HPV-positive), and two healthy fibroblast cell lines, SBLF8 and SBLF9, were studied. Flow cytometry was used to analyze apoptosis and necrosis induction (AnnexinV/7AAD) and cell cycle distribution (Hoechst). Cell inactivation was studied by the colony-forming assay. (3) AZD7648 had the strongest effects, radiosensitizing all HNSCC cell lines, almost always in a supra-additive manner. Talazoparib and niraparib were effective in both HPV-positive cell lines but only consistently in one and two HPV-negative cell lines, respectively. Healthy fibroblasts were not affected by any combined treatment in apoptosis and necrosis induction or G2/M-phase arrest. AZD7648 alone was not toxic to healthy fibroblasts, while the combination with ionizing radiation reduced clonogenicity. (4) In conclusion, talazoparib, niraparib and, most potently, AZD7648 could improve radiation therapy in HNSCC. Healthy fibroblasts tolerated AZD7648 alone extremely well, but irradiation-induced effects might occur. Our results justify in vivo studies.
(1) 头颈部鳞状细胞癌（HNSCC）较为常见，治疗困难，死亡率高。激酶抑制剂有望增强放疗效果。我们比较了 PARP 抑制剂他拉唑帕尼和尼拉帕尼以及 DNA-PKcs 抑制剂 AZD7648 与电离辐射联合的效果。(2) 研究了包括 Cal33、CLS-354、Detroit 562、HSC4、RPMI2650（HPV 阴性）、UD-SCC-2 和 UM-SCC-47（HPV 阳性）在内的 7 种 HNSCC 细胞系和 2 种健康成纤维细胞系 SBLF8 和 SBLF9。采用流式细胞术分析细胞凋亡和坏死诱导（AnnexinV/7AAD）和细胞周期分布（Hoechst）。通过集落形成实验研究细胞失活。(3) AZD7648 作用最强，使所有 HNSCC 细胞系均具有放射增敏作用，几乎总是呈超相加方式。他拉唑帕尼和尼拉帕尼在两种 HPV 阳性细胞系中均有效，但分别仅在一种和两种 HPV 阴性细胞系中始终有效。健康成纤维细胞在诱导凋亡和坏死或 G2/M 期阻滞方面不受任何联合治疗的影响。AZD7648 单独使用对健康成纤维细胞没有毒性，而与电离辐射联合使用会降低集落形成能力。(4) 总之，他拉唑帕尼、尼拉帕尼和最有效的 AZD7648 均可改善 HNSCC 的放射治疗效果。健康成纤维细胞对 AZD7648 单独使用的耐受性非常好，但可能会发生辐射诱导的作用。我们的结果证明了体内研究的合理性。
