(1)头颈部鳞状细胞癌(HNSCC)是常见的,虽然治疗很困难,死亡率很高。激酶抑制剂有望增强放射治疗的效果。我们比较了PARP抑制剂talazoparib和niraparib以及DNA-PKcs抑制剂AZD7648联合电离辐射的效果。(2)七个HNSCC细胞系,包括Cal33,CLS-354,底特律562,HSC4,RPMI2650(HPV阴性),UD-SCC-2和UM-SCC-47(HPV阳性),和两个健康的成纤维细胞细胞系,研究了SBLF8和SBLF9。流式细胞术用于分析凋亡和坏死诱导(AnnexinV/7AAD)和细胞周期分布(Hoechst)。通过集落形成测定法研究细胞失活。(3)AZD7648效应最强,放射增敏所有HNSCC细胞系,几乎总是以超相加的方式。Talazoparib和niraparib在两种HPV阳性细胞系中均有效,但仅在一种和两种HPV阴性细胞系中均有效。分别。健康的成纤维细胞不受凋亡和坏死诱导或G2/M期停滞的任何联合治疗的影响。AZD7648单独对健康成纤维细胞没有毒性,而与电离辐射的结合降低了克隆性。(4)总之,talazoparib,尼拉帕利和,最有力的,AZD7648可以改善HNSCC的放射治疗。健康的成纤维细胞单独耐受AZD7648非常好,但是辐射诱导的效应可能会发生。我们的结果证明了体内研究的正确性。
(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.