Dual mTOR/DNA-PK Inhibitor CC-115 Induces Cell Death in Melanoma Cells and Has Radiosensitizing Potential.
Cell Death
/ drug effects
Cell Line
Cell Line, Tumor
DNA-Activated Protein Kinase
/ antagonists & inhibitors
Fibroblasts
/ drug effects
Homologous Recombination
Humans
Melanoma
/ metabolism
Protein Kinase Inhibitors
/ pharmacology
Pyrazines
/ pharmacology
Radiation Tolerance
/ drug effects
TOR Serine-Threonine Kinases
/ antagonists & inhibitors
Triazoles
/ pharmacology
DNA repair
DNA-PK
homologous recombination (HR)
kinase inhibitor
mTOR
melanoma
non-homologous end-joining (NHEJ)
radiosensitivity
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
07 Dec 2020
07 Dec 2020
Historique:
received:
10
11
2020
revised:
03
12
2020
accepted:
05
12
2020
entrez:
10
12
2020
pubmed:
11
12
2020
medline:
3
3
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33297429
pii: ijms21239321
doi: 10.3390/ijms21239321
pmc: PMC7730287
pii:
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Pyrazines
0
Triazoles
0
DNA-Activated Protein Kinase
EC 2.7.11.1
PRKDC protein, human
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino(2,3-b)pyrazin-2(1H)-one
FII75TFH5L
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
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