Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells
Open accessAbstract
We used synthetic lethal high-throughput screening to interrogate 23,550 compounds for their ability to kill engineered tumorigenic cells but not their isogenic normal cell counterparts. We identified known and novel compounds with genotype-selective activity, including doxorubicin, daunorubicin, mitoxantrone, camptothecin, sangivamycin, echinomycin, bouvardin, NSC146109, and a novel compound that we named erastin. These compounds have increased activity in the presence of hTERT, the SV40 large and small T oncoproteins, the human papillomavirus type 16 (HPV) E6 and E7 oncoproteins, and oncogenic HRAS. We found that overexpressing hTERT and either E7 or LT increased expression of topoisomerase 2alpha and that overexpressing RAS(V12) and ST both increased expression of topoisomerase 1 and sensitized cells to a nonapoptotic cell death process initiated by erastin.
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Erastin- and RSL3-induced death is non-apoptotic, occurring without apoptotic hallmarks and even when core apoptosis machinery is suppressed.
“The mode of cell death induced by these compounds was surprisingly found to be non-apoptotic, as cells treated with erastin and RSL3 died in the absence of apoptotic hallmarks [11, 12, 13], and in cells where the core apoptosis machinery – caspases, BAX, and BAK was suppressed [14].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [11]
Erastin and RSL3 were the first compounds found to induce ferroptosis, identified through high-throughput small-molecule screening.
“The first ferroptosis-inducing compounds, erastin [11] and RSL3 [12], were discovered using high-throughout screening of small molecule libraries [11, 12].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [11]
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- Authors
- Dolma, S., Lessnick, S. L., Hahn, W. C., & Stockwell, B. R.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Boston Children's Hospital (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Stockwell, Brent R
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2003-03
- Volume
- 3
- Issue
- 3
- Pages
- 285-296
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2057632732
- Cited by
- 1,446
- References
- 2
- Citations by year
- 2026: 92 · 2025: 163 · 2024: 244 · 2023: 214 · 2022: 172 · 2021: 156 · 2020: 95 · 2019: 59 · 2018: 36 · 2017: 41 · 2016: 21 · 2015: 15 · 2014: 20 · 2013: 15 · 2012: 14
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Burroughs Wellcome Fund
- Doris Duke Charitable Foundation
- National Institutes of Health
- National Cancer Institute (1R01CA97061-01, K08CA096755, R01CA097061, 1K08CA96755-01, K01CA94223, K01CA094223)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- synthetic lethality, high-throughput compound screening, erastin, topoisomerase I, hTERT, SV40 T antigen, HPV E6 and E7 oncoproteins, non-apoptotic cell death, doxorubicin, camptothecin, topoisomerase inhibitors, drug repurposing
- MeSH terms
- Antineoplastic Agents, Cell Line, Cell Transformation, Viral, Drug Screening Assays, Antitumor, Fibroblasts, Fluoresceins, Fluorescent Dyes, Genetic Engineering, Genotype, Humans, Piperazines, Retroviridae, Tumor Cells, Cultured, Molecular Structure, Oncogene Proteins, Gene Expression Regulation, Neoplastic, Cell Death, Inhibitory Concentration 50
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