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Development of a G2/M arrest high-throughput screening method identifies potent radiosensitizers.

ABSTRACT: Radiation is a powerful tool used to control tumor growth and induce an immune response; however, it is limited by damage to surrounding tissue and adverse effects such skin irritation. Breast cancer patients in particular may endure radiation dermatitis, and potentially lymphedema, after a course of radiotherapy. Radio-sensitizing small molecule drugs may enable lower effective doses of both radiation and chemotherapy to minimize toxicity to healthy tissue. In this study, we identified a novel high-throughput method for screening radiosensitizers by image analysis of nuclear size and cell cycle. In vitro assays were performed on cancer cells lines to assess combined therapeutic and radiation effects. In vivo, radiation in combination with proflavine hemisulfate led to enhanced efficacy demonstrated by improved tumor volume control in mice bearing syngeneic breast tumors. This study provides a proof of concept for utilizing G2/M stall as a predictor of radiosensitization and is the first report of a flavin acting as an X-ray radiation enhancer in a breast cancer mouse model.

SUBMITTER: Landry M

PROVIDER: S-EPMC8732089 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Development of a G2/M arrest high-throughput screening method identifies potent radiosensitizers.

Landry Madeleine M Nelson Dylan D Choi Eunseo E DuRoss Allison A Sun Conroy C

Translational oncology 20220102

Radiation is a powerful tool used to control tumor growth and induce an immune response; however, it is limited by damage to surrounding tissue and adverse effects such skin irritation. Breast cancer patients in particular may endure radiation dermatitis, and potentially lymphedema, after a course of radiotherapy. Radio-sensitizing small molecule drugs may enable lower effective doses of both radiation and chemotherapy to minimize toxicity to healthy tissue. In this study, we identified a novel ...[more]

PMID: 34986454

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Project description:BACKGROUND: Previous studies from our laboratory and others have demonstrated that in addition to altering chromatin acetylation and conformation, histone deacetylase inhibitors (HDACi) disrupt the acetylation status of numerous transcription factors and other proteins. A whole genome yeast deletion library screen was used to identify components of the transcriptional apparatus that modulate the sensitivity to the hydroxamic acid-based HDACi, CG-1521. RESULTS: Screening 4852 haploid Saccharomyces cerevisiae deletion strains for sensitivity to CG-1521 identifies 407 sensitive and 80 resistant strains. Gene ontology (GO) enrichment analysis shows that strains sensitive to CG-1521 are highly enriched in processes regulating chromatin remodeling and transcription as well as other ontologies, including vacuolar acidification and vesicle-mediated transport. CG-1521-resistant strains include those deficient in the regulation of transcription and tRNA modification. Components of the SAGA histone acetyltransferase (HAT) complex are overrepresented in the sensitive strains, including the catalytic subunit, Gcn5. Cell cycle analysis indicates that both the wild-type and gcn5? strains show a G1 delay after CG-1521 treatment, however the gcn5? strain displays increased sensitivity to CG-1521-induced cell death compared to the wild-type strain. To test whether the enzymatic activity of Gcn5 is necessary in the response to CG-1521, growth assays with a yeast strain expressing a catalytically inactive variant of the Gcn5 protein were performed and the results show that this strain is less sensitive to CG-1521 than the gcn5? strain. CONCLUSION: Genome-wide deletion mutant screening identifies biological processes that affect the sensitivity to the HDAC inhibitor CG-1521, including transcription and chromatin remodeling. This study illuminates the pathways involved in the response to CG-1521 in yeast and provides incentives to understand the mechanisms of HDAC inhibitors in cancer cells. The data presented here demonstrate that components of the SAGA complex are involved in mediating the response to CG-1521. Additional experiments suggest that functions other than the acetyltransferase activity of Gcn5 may be sufficient to attenuate the effects of CG-1521 on cell growth.

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Development of a G2/M arrest high-throughput screening method identifies potent radiosensitizers.

Publications

Development of a G2/M arrest high-throughput screening method identifies potent radiosensitizers.

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