Salinomycin promotes T-cell proliferation by inhibiting the expression and enzymatic activity of immunosuppressive indoleamine-2,3-dioxygenase in human breast cancer cells.

Salinomycin promotes T-cell proliferation by inhibiting the expression and enzymatic activity of immunosuppressive indoleamine-2,3-dioxygenase in human breast cancer cells. Toxicol Appl Pharmacol. 2020 Aug 18;:115203 Authors: Ebokaiwe AP, Njoya EM, Sheng Y, Zhang Z, Sheng L, Zhou Z, Qiang Z, Ting P, Hussein AA, Zhang G, Lu X, Li L, Wang F Abstract Indoleamine 2,3 dioxygenase (IDO) is upregulated in many tumor types, including breast cancer, and plays a reputable role in promoting tumor immune tolerance. The importance of the immunosuppressive mechanism of IDO by suppressing T-cell function has garnered profound interest in the development of clinical IDO inhibitors. Herein, we established a screening method with cervical HeLa cells to induce IDO expression using interferon-γ (IFN-γ). After screening our chemical library, we found that salinomycin potently inhibited IFN-γ-stimulated kynurenine synthesis with IC50 values of 3.36-4.66 μM in both human cervical and breast cancer cells. Salinomycin lowered the IDO1 and IDO2 expression with no impact on the expression of tryptophan-2,3-dioxygenase. Interestingly, salinomycin potently repressed the IDO1 enzymatic activity by directly targeting the proteins in cells. Molecular docking revealed an alignment that favors nucleophilic attack of salinomycin in the catalytic domain of IDO1. Activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway by ...
Source: Toxicology and Applied Pharmacology - Category: Toxicology Authors: Tags: Toxicol Appl Pharmacol Source Type: research