Combination screen in multi-cell type tumor spheroids reveals interaction between aryl hydrocarbon receptor antagonists and E1 ubiquitin-activating enzyme inhibitor.

Autor:	Dexheimer TS; Target Validation and Screening Laboratory, Molecular Pharmacology Laboratory, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, 1050 Boyles Street, Frederick, MD 21702, USA. Electronic address: thomas.dexheimer@nih.gov., Coussens NP; Target Validation and Screening Laboratory, Molecular Pharmacology Laboratory, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, 1050 Boyles Street, Frederick, MD 21702, USA., Silvers T; Target Validation and Screening Laboratory, Molecular Pharmacology Laboratory, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, 1050 Boyles Street, Frederick, MD 21702, USA., Jones EM; Target Validation and Screening Laboratory, Molecular Pharmacology Laboratory, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, 1050 Boyles Street, Frederick, MD 21702, USA., Chen L; Molecular Characterization Laboratory, Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Fang J; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Morris J; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Moscow JA; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Doroshow JH; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Teicher BA; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Jazyk:	angličtina
Zdroj:	SLAS discovery : advancing life sciences R & D [SLAS Discov] 2024 Oct; Vol. 29 (7), pp. 100186. Date of Electronic Publication: 2024 Oct 01.
DOI:	10.1016/j.slasd.2024.100186
Abstrakt:	The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates genes of drug transporters and metabolic enzymes to detoxify small molecule xenobiotics. It has a complex role in cancer biology, influencing both the progression and suppression of tumors by modulating malignant properties of tumor cells and anti-tumor immunity, depending on the specific tumor type and developmental stage. This has led to the discovery and development of selective AhR modulators, including BAY 2416964 which is currently in clinical trials. To identify small molecule anticancer agents that might be combined with AhR antagonists for cancer therapy, a high-throughput combination screen was performed using multi-cell type tumor spheroids grown from malignant cells, endothelial cells, and mesenchymal stem cells. The AhR selective antagonists BAY 2416964, GNF351, and CH-223191 were tested individually and in combination with twenty-five small molecule anticancer agents. As single agents, BAY 2416964 and CH-223191 showed minimal activity, whereas GNF351 reduced the viability of some spheroid models at concentrations greater than 1 µM. The activity of most combinations aligned well with the single agent activity of the combined agent, without apparent contributions from the AhR antagonist. All three AhR antagonists sensitized tumor spheroids to TAK-243, an E1 ubiquitin-activating enzyme inhibitor. These combinations were active in spheroids containing bladder, breast, ovary, kidney, pancreas, colon, and lung tumor cell lines. The AhR antagonists also potentiated pevonedistat, a selective inhibitor of the NEDD8-activating enzyme E1 regulatory subunit, in several tumor spheroid models. In contrast, the AhR antagonists did not enhance the cytotoxicity of the proteasome inhibitor bortezomib. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024. Published by Elsevier Inc.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu