Dual mTOR/DNA-PK Inhibitor CC-115 Induces Cell Death in Melanoma Cells and Has Radiosensitizing Potential.
Dual mTOR/DNA-PK Inhibitor CC-115 Induces Cell Death in Melanoma Cells and Has Radiosensitizing Potential.
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DOI：
10.3390/ijms21239321
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发表时间：
2020-12-07
影响因子：
5.6
通讯作者：
Distel L
中科院分区：
文献类型：
--
作者：
Bürkel F;Jost T;Hecht M;Heinzerling L;Fietkau R;Distel L
CC-115是雷帕霉素(MTOR)激酶和DNA依赖蛋白激酶(DNA-PK)机制靶点的双重抑制剂，目前正在进行I/II期临床试验。DNA-PK对于DNA双链断裂(DSB)的修复是必不可少的。放射治疗常用于转移性黑色素瘤患者的姑息治疗，并诱发DSB。用CC-115和电离辐射(IR)处理黑色素瘤细胞系和健康供体皮肤成纤维细胞系。分析细胞的凋亡、坏死及细胞周期分布。采用集落形成实验研究放射增敏作用。免疫荧光显微镜检测同源重组(HR)活性。在大多数恶性细胞系中，CC-115浓度的增加导致细胞死亡增加。此外，仅在恶性细胞系中观察到较强的细胞毒作用。在克隆形成方面，在抑制剂和IR联合作用下，所有细胞株的存活分数都降低了，并且在9个黑色素瘤细胞系中有5个细胞株观察到了超相加效应。CC-115在9个黑色素瘤细胞系中有7个显示出放射增敏潜力，但在健康皮肤成纤维细胞中不显示。根据我们的数据，CC-115治疗可能是转移性黑色素瘤患者的一种有前途的方法，特别是在与放射治疗相结合的情况下。
CC-115 is a dual inhibitor of the mechanistic target of rapamycin (mTOR) kinase and the DNA-dependent protein kinase (DNA-PK) that is currently being studied in phase I/II clinical trials. DNA-PK is essential for the repair of DNA-double strand breaks (DSB). Radiotherapy is frequently used in the palliative treatment of metastatic melanoma patients and induces DSBs. Melanoma cell lines and healthy-donor skin fibroblast cell lines were treated with CC-115 and ionizing irradiation (IR). Apoptosis, necrosis, and cell cycle distribution were analyzed. Colony forming assays were conducted to study radiosensitizing effects. Immunofluorescence microscopy was performed to determine the activity of homologous recombination (HR). In most of the malign cell lines, an increasing concentration of CC-115 resulted in increased cell death. Furthermore, strong cytotoxic effects were only observed in malignant cell lines. Regarding clonogenicity, all cell lines displayed decreased survival fractions during combined inhibitor and IR treatment and supra-additive effects of the combination were observable in 5 out of 9 melanoma cell lines. CC-115 showed radiosensitizing potential in 7 out of 9 melanoma cell lines, but not in healthy skin fibroblasts. Based on our data CC-115 treatment could be a promising approach for patients with metastatic melanoma, particularly in the combination with radiotherapy.
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影响因子：
19
作者：
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通讯作者：
D'Andrea AD
影响因子：
6.2
作者：
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通讯作者：
Barton, M
影响因子：
3.1
作者：
Burjakow, Kim;Fietkau, Rainer;Knippen, Stefan
通讯作者：
Knippen, Stefan
影响因子：
6
作者：
Dobler C;Jost T;Hecht M;Fietkau R;Distel L
通讯作者：
Distel L
DOI：
10.1016/s1470-2045(17)30429-1
发表时间：
2017-07
期刊：
The Lancet. Oncology
影响因子：
--
作者：
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通讯作者：
Long GV