Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells.

By Sonam Dolma, S. Lessnick, William C. Hahn, Brent R. Stockwell. Cancer Cell, 2003

1,178 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/5e0991d7c46b21dfd21b25b67faf24f9a799f3ac

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Citations in the corpus

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “Some of the molecular circuitries regulating the initial steps of ferroptosis have been recently unveiled by employing (1) specific ferroptosis-inducing agents, including erastin [543, 544], RSL3 [543, 544], and FIN56 [545]; and (2) specific ferroptosis-inhibiting agents, including ferrostatins [539”
Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, positive): “(for eradicator of RAS-transformed cells), that induced nonapoptotic cell death (Dolma et al., 2003) that depended on the accumulation of oxidative stress and cellular iron levels (Yagoda et al.”
Regulation of Ferroptotic Cancer Cell Death by GPX4 (2014, background): “In engineered human fibroblast cell lines, the small molecule erastin was found to induce preferential lethality in cells overexpressing oncogenic HRAS (Dolma et al., 2003).”
The Tumor Suppressor Protein p53 and the Ferroptosis Network (2018, positive): “Erastin, the first inducer of ferroptosis, was identified through a high-throughput small molecule screening searching for agents that selectively killed RAS mutated cancer cells, including H-Ras-mutant engineered human foreskin fibroblasts (BJeLR), N-Ras-mutant HT-1080 cells (a fibrosarcoma cell li”