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Article

Dual mTOR/DNA-PK Inhibitor CC-115 Induces Cell Death in Melanoma Cells and Has Radiosensitizing Potential

1
Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 27, 91054 Erlangen, Germany
2
Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(23), 9321; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239321
Received: 10 November 2020 / Revised: 3 December 2020 / Accepted: 5 December 2020 / Published: 7 December 2020
(This article belongs to the Special Issue Multikinase Inhibitors and Cancer)
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. View Full-Text
Keywords: DNA-PK; mTOR; melanoma; DNA repair; radiosensitivity; non-homologous end-joining (NHEJ); homologous recombination (HR); kinase inhibitor DNA-PK; mTOR; melanoma; DNA repair; radiosensitivity; non-homologous end-joining (NHEJ); homologous recombination (HR); kinase inhibitor
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MDPI and ACS Style

Bürkel, F.; Jost, T.; Hecht, M.; Heinzerling, L.; Fietkau, R.; Distel, L. Dual mTOR/DNA-PK Inhibitor CC-115 Induces Cell Death in Melanoma Cells and Has Radiosensitizing Potential. Int. J. Mol. Sci. 2020, 21, 9321. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239321

AMA Style

Bürkel F, Jost T, Hecht M, Heinzerling L, Fietkau R, Distel L. Dual mTOR/DNA-PK Inhibitor CC-115 Induces Cell Death in Melanoma Cells and Has Radiosensitizing Potential. International Journal of Molecular Sciences. 2020; 21(23):9321. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239321

Chicago/Turabian Style

Bürkel, Felix, Tina Jost, Markus Hecht, Lucie Heinzerling, Rainer Fietkau, and Luitpold Distel. 2020. "Dual mTOR/DNA-PK Inhibitor CC-115 Induces Cell Death in Melanoma Cells and Has Radiosensitizing Potential" International Journal of Molecular Sciences 21, no. 23: 9321. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239321

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