Related Experiment Video
Updated: Jul 15, 2025
Genome-Wide CRISPR Screen for Unveiling Radiosensitive and Radioresistant Genes
Published on: May 23, 2025
Integrated High-Throughput Screening and Large-Scale Isobolographic Analysis to Accelerate the Discovery of
Pierre Verrelle1, Pierre Gestraud2, Florent Poyer2
1Radiation Oncology Department, Institut Curie Hospital, Paris, France; Chemistry and Modelisation for the Biology of Cancer, CNRS UMR9187, INSERM U1196, Institut Curie, Université Paris Saclay, 91405 Orsay, France.
Purpose:
High-throughput screening (HTS) platforms have been widely used to identify candidate anticancer drugs and drug-drug combinations; however, HTS-based identification of new drug-ionizing radiation (IR) combinations has rarely been reported. Herein, we developed an integrated approach including cell-based HTS and computational large-scale isobolographic analysis to accelerate the identification of radiosensitizing compounds acting strongly and more specifically on cancer cells.
Methods And Materials:
In a 384-well plate format, 160 compounds likely to interfere with the cell response to radiation were screened on human glioblastoma (U251-MG) and cervix carcinoma (ME-180) cell lines, as well as on normal fibroblasts (CCD-19Lu). After drug exposure, cells were irradiated or not and short-term cell survival was assessed by high-throughput cell microscopy. Computational large-scale dose-response and isobolographic approach were used to identify promising synergistic drugs radiosensitizing cancer cells rather than normal cells. Synergy of a promising compound was confirmed on ME-180 cells by an independent 96-well assay protocol, and finally, by the gold-standard colony forming assay.
Results:
We retained 4 compounds synergistic at 2 isoeffects in U251-MG and ME-180 cell lines and 11 compounds synergistically effective in only one cancer cell line. Among these 15 promising radiosensitizers, 5 compounds showed limited toxicity combined or not with IR on normal fibroblasts.
Conclusions:
Overall, this study demonstrated that HTS chemoradiation screening together with large-scale computational analysis is an efficient tool to identify synergistic drug-IR combinations, with concomitant assessment of unwanted toxicity on normal fibroblasts. It sparks expectations to accelerate the discovery of highly desired agents improving the therapeutic index of radiation therapy.
Insights
This study developed a high-throughput screening method to find new drug-ionizing radiation combinations that enhance cancer treatment. The approach efficiently identifies radiosensitizing compounds with reduced toxicity to normal cells.
Area of Science:
- Oncology
- Radiotherapy
- Drug Discovery
Background:
- High-throughput screening (HTS) is crucial for identifying anticancer drugs and combinations.
- However, HTS for drug-ionizing radiation (IR) combinations is less explored.
- Developing novel radiosensitizers is key to improving radiation therapy's efficacy.
Purpose of the Study:
- To develop an integrated approach for identifying synergistic drug-IR combinations.
- To accelerate the discovery of radiosensitizing compounds with cancer-specific activity.
- To assess the toxicity of identified compounds on normal cells.
Main Methods:
- A cell-based HTS platform screened 160 compounds on glioblastoma, cervix carcinoma, and normal fibroblast cell lines.
- Cells were exposed to drugs and/or ionizing radiation (IR).
- Computational large-scale isobolographic analysis identified synergistic radiosensitizers, with validation via colony formation assays.
Main Results:
- 15 promising radiosensitizing compounds were identified across two cancer cell lines.
- Four compounds showed synergy in both cancer cell lines.
- Five compounds exhibited limited toxicity to normal fibroblasts when combined with IR.
Conclusions:
- HTS combined with computational analysis is effective for identifying synergistic drug-IR combinations.
- This approach allows for the assessment of toxicity on normal cells.
- The study accelerates the discovery of agents to improve radiation therapy's therapeutic index.
More Related Videos
10:13A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells
Published on: July 3, 2013
07:48Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
Published on: December 26, 2016