Isoliquiritin modulates ferroptosis via NF-κB signaling inhibition and alleviates doxorubicin resistance in breast cancer

Abstract

Context

Breast cancer (BC) is the most prevalent diagnosed tumor and the major reason for tumor-related death in females around the world. Isoliquiritin, a type of plant extract, has exhibited a probable inhibitory effect in a variety of cancers. However, the anti-tumor effect on BC is still unclear.

Objective

To reveal the effect and potential mechanism of Isoliquiritin on BC.

Materials and methods

The cell viabilities were detected by CCK-8 assay. The levels of indicators of ferroptosis, oxidative stress, glycolysis, and inflammation were evaluated by commercial kits, flow cytometry, western blot, spectrophotometry, and ELISA assays. Mechanically, the expressions expression of the NF-κB pathway was determined by western blot. In vivo assay was also yielded on the BALB/c nude mice.

Results

Iso induced a concentration and time-dependent decrease of viability in both MDA-MB-231 and MCF-7 cells. Iso treatment significantly increased the levels of Fe²⁺, ROS, and MDA, and decreased the GSH level, and the relative protein expressions of GPX4 and xCT. Furthermore, Iso modulated oxidative stress, glycolysis, and inflammation through ferroptosis. In addition, Iso induced a concentration-dependent decrease in cell viability and a concentration-dependent increase in apoptosis rate in both MDA-MB-231/Dox and MCF-7/Dox cells. Iso notably counteracted the LPS-induced relative protein levels of p-p50/p50, p-p65/p65, and IκB, and the levels of ferroptosis, oxidative stress, glycolysis, and inflammation. The same results were also verified in vivo.

Conclusion

Iso inhibited the NF-κB signaling to regulate ferroptosis and improved Dox-resistance in breast cancer.

Keywords:

• Breast cancer
• isoliquiritin
• ferroptosis
• metabolism
• resistance
• NF-κB

Author contributions

JW: Conceptualization, Writing-Original draft preparation, Investigation, Validation, and Supervision; YL: Data curation and Methodology; JZ: Visualization and Software; CL: Writing-Reviewing and Editing; Approval of final manuscript: All authors.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data determined and used during the present study are available from the corresponding author on reasonable request.

Additional information

Funding

This study is supported by the 2019 Bao’an District Medical and Health Basic Research Project (Grant number: 2019JD333).