Multiparametric High-Content Cell Painting Identifies Copper Ionophores as Selective Modulators of Esophageal Cancer Phenotypes
- Author(s)
- Hughes, RE; Elliott, RJR; Li, X; Munro, AF; Makda, A; Carter, RN; Morton, NM; Fujihara, K; Clemons, NJ; Fitzgerald, R; O'Neill, JR; Hupp, T; Carragher, NO;
- Details
- Publication Year 2022-07-15,Volume 17,Issue #7,Page 1876-1889
- Journal Title
- ACS Chemical Biology
- Publication Type
- Research article
- Abstract
- Esophageal adenocarcinoma is of increasing global concern due to increasing incidence, a lack of effective treatments, and poor prognosis. Therapeutic target discovery and clinical trials have been hindered by the heterogeneity of the disease, the lack of "druggable" driver mutations, and the dominance of large-scale genomic rearrangements. We have previously undertaken a comprehensive small-molecule phenotypic screen using the high-content Cell Painting assay to quantify the morphological response to a total of 19,555 small molecules across a panel of genetically distinct human esophageal cell lines to identify new therapeutic targets and small molecules for the treatment of esophageal adenocarcinoma. In this current study, we report for the first time the dose-response validation studies for the 72 screening hits from the target-annotated LOPAC and Prestwick FDA-approved compound libraries and the full list of 51 validated esophageal adenocarcinoma-selective small molecules (71% validation rate). We then focus on the most potent and selective hit molecules, elesclomol, disulfiram, and ammonium pyrrolidinedithiocarbamate. Using a multipronged, multitechnology approach, we uncover a unified mechanism of action and a vulnerability in esophageal adenocarcinoma toward copper-dependent cell death that could be targeted in the future.
- Keywords
- *Adenocarcinoma/drug therapy; Copper/metabolism; *Esophageal Neoplasms/drug therapy; Humans; Ionophores/pharmacology; Phenotype
- Department(s)
- Laboratory Research
- PubMed ID
- 35696676
- Publisher's Version
- https://doi.org/10.1021/acschembio.2c00301
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-12-13 04:26:01
Last Modified: 2024-12-13 04:27:13