Senescence Induction by Combined Ionizing Radiation and DNA Damage Response Inhibitors in Head and Neck Squamous Cell Carcinoma Cells.
Senescence Induction by Combined Ionizing Radiation and DNA Damage Response Inhibitors in Head and Neck Squamous Cell Carcinoma Cells.
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DOI：
10.3390/cells9092012
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发表时间：
2020-09-01
期刊：
影响因子：
6
通讯作者：
Distel L
中科院分区：
文献类型：
--
作者：
Dobler C;Jost T;Hecht M;Fietkau R;Distel L
DNA损伤反应抑制剂（DDRi）与电离辐射（IR）联合应用可选择性地增强肿瘤细胞的失活。衰老的诱导可能是这种组合治疗中肿瘤细胞灭活的关键机制。在当前的研究中，在具有不同人乳头瘤病毒（HPV）状态的头颈部鳞状细胞癌（HNSCC）细胞中研究了IR与DDRi组合对衰老诱导的影响。在两种HPV阳性、两种HPV阴性HNSCC和两种健康成纤维细胞培养物中评估同源重组（HR）的完整性。用DDRi CC-115（DNA依赖性蛋白激酶，DNA-pK;雷帕霉素的双重哺乳动物靶标，mTor）、VE-822（ATR;共济失调毛细血管扩张和Rad 3相关激酶）和AZD 0156（ATM;共济失调毛细血管扩张突变激酶）与IR组合处理细胞。通过流式细胞术分析对衰老、凋亡、坏死和细胞周期的影响。成纤维细胞系一般耐受IR或联合治疗优于肿瘤细胞系。ATM和ATR抑制剂与IR联用可有效诱导衰老，DNA-PK抑制剂不是重要的衰老诱导剂。HPV状态和HR活性对DDRi疗效的影响有限。由于分子异质性和衰老诱导中DNA损伤反应途径的参与，衰老和坏死的诱导在细胞系中各不相同。
DNA damage response inhibitors (DDRi) may selectively enhance the inactivation of tumor cells in combination with ionizing radiation (IR). The induction of senescence may be the key mechanism of tumor cell inactivation in this combinatorial treatment. In the current study the effect of combined IR with DDRi on the induction of senescence was studied in head and neck squamous cell carcinoma (HNSCC) cells with different human papilloma virus (HPV) status. The integrity of homologous recombination (HR) was assessed in two HPV positive, two HPV negative HNSCC, and two healthy fibroblast cell cultures. Cells were treated with the DDRi CC-115 (DNA-dependent protein kinase, DNA-pK; dual mammalian target of rapamycin, mTor), VE-822 (ATR; ataxia telangiectasia and Rad3-related kinase), and AZD0156 (ATM; ataxia telangiectasia mutated kinase) combined with IR. Effects on senescence, apoptosis, necrosis, and cell cycle were analyzed by flow cytometry. The fibroblast cell lines generally tolerated IR or combined treatment better than the tumor cell lines. The ATM and ATR inhibitors were effectively inducing senescence when combined with IR. The DNA-PK inhibitor was not an important inductor of senescence. HPV status and HR activity had a limited influence on the efficacy of DDRi. Induction of senescence and necrosis varied individually among the cell lines due to molecular heterogeneity and the involvement of DNA damage response pathways in senescence induction.
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DOI：
10.18632/aging.100443
发表时间：
2012-03
期刊：
Aging
影响因子：
--
作者：
Blagosklonny MV
通讯作者：
Blagosklonny MV
影响因子：
5.6
作者：
Castilho RM;Squarize CH;Almeida LO
通讯作者：
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影响因子：
4.7
作者：
Hafsi H;Dillon MT;Barker HE;Kyula JN;Schick U;Paget JT;Smith HG;Pedersen M;McLaughlin M;Harrington KJ
通讯作者：
Harrington KJ
DOI：
10.1016/j.radonc.2017.09.043
发表时间：
2018-03
期刊：
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
影响因子：
--
作者：
Qiu Z;Oleinick NL;Zhang J
通讯作者：
Zhang J
影响因子：
11.5
作者：
Mukhopadhyay, Asima;Elattar, Ahmed;Curtin, Nicola J.
通讯作者：
Curtin, Nicola J.