Thippu Jayaprakash, K;
Hussein, M;
Shaffer, R;
Michael, A;
Nisbet, A;
Ajaz, M;
(2021)
In Vitro Evaluation of Notch Inhibition to Enhance Efficacy of Radiation Therapy in Melanoma.
Advances in Radiation Oncology
, 6
(2)
, Article 100622. 10.1016/j.adro.2020.11.007.
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Abstract
PURPOSE: The scope of radiation therapy is limited in melanoma. Using in vitro melanoma models, we investigated a Notch signaling inhibitor as a radiosensitizer to explore its potential to improve the efficacy of radiation therapy to widen the clinical application of radiation therapy in melanoma. METHODS AND MATERIALS: Melanoma cell lines A375, SKMEL28, and G361 were grown using standard tissue culture methods. Radiation was delivered with a clinical x-ray unit, and a gamma secretase inhibitor RO4929097 was used to inhibit Notch signaling. Cell viability signal was used to calculate Loewe’s combination index to assess the interaction between radiation and RO4929097 and also the effect of scheduling of radiation and RO4929097 on synergy. Clonogenic assays were used to assess the clonogenic potential. An in vitro 3-dimensional culture model, γ-H2AX, and notch intracellular domain assays were used to interrogate potential underlying biological mechanisms of this approach. Scratch and transwell migration assays were used to assess cell migration. RESULTS: A375 and SKMEL28 cell lines showed consistent synergy for most single radiation doses examined, with a tendency for better synergy with the radiation-first schedule (irradiation performed 24 hours before RO4929097 exposure). Clonogenic assays showed dose-dependent reduction in colony numbers. Both radiation and RO4929097 reduced the size of melanospheres grown in 3-dimensional culture in vitro, where RO4929097 demonstrated a significant effect on the size of A375 and SKMEL28 melanospheres, indicating potential modulation of stem cell phenotype. Radiation induced γ-H2AX foci signal levels were reduced after exposure to RO4929097 with a tendency toward reduction in notch intracellular domain levels for all 3 cell lines. RO4929097 impaired both de novo and radiation-enhanced cell migration. CONCLUSIONS: We demonstrate Notch signaling inhibition with RO4929097 as a promising strategy to potentially improve the efficacy of radiation therapy in melanoma. This strategy warrants further validation in vivo.
| Type: | Article |
|---|---|
| Title: | In Vitro Evaluation of Notch Inhibition to Enhance Efficacy of Radiation Therapy in Melanoma |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.adro.2020.11.007 |
| Publisher version: | https://doi.org/10.1016/j.adro.2020.11.007 |
| Language: | English |
| Additional information: | © 2020 The Author(s). Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Med Phys and Biomedical Eng |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10124395 |
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