Idebenone Exerts anti-Triple Negative Breast Cancer Effects via Dual Signaling Pathways of GADD45 and AMPK

Abstract

Idebenone, a mitochondrial regulator, has exhibited anti-cancer activity in neurogenic and prostate tumor cells; however, its efficacy and specific targets in the treatment of triple-negative breast cancer (TNBC) remain unclear. This study aims to evaluate the potential of Idebenone as a therapeutic agent for TNBC. TNBC cell lines and Xenograft mouse models were used to assess the effect of Idebenone on TNBC both in vitro and in vivo. To investigate the underlying mechanism of Idebenone’s effect on TNBC, cell viability assay, transwell invasion assay, cell cycle analysis, apoptosis assay, mitochondrial membrane potential assay, immunofluorescence staining, and transcriptome sequencing were utilized. The results showed that Idebenone impeded the proliferation, colony formation, migration, and invasion of TNBC cells, suppressed apoptosis, and halted the cell cycle in the G2/M phase. The inhibitory effect of Idebenone on TNBC was associated with the GADD45/CyclinB/CDK1 signaling pathway. By disrupting the mitochondrial membrane potential (MMP) and promoting mitophagy, Idebenone promoted cell autophagy through the AMPK/mTOR pathway, thus further suppressing the proliferation of TNBC cells. Furthermore, we found that Idebenone inhibited the development of TNBC in vivo. In conclusion, Idebenone may be a promising therapeutic option for TNBC as it is capable of inducing autophagy and apoptosis.

Authors’ Contribution

YZ and FY conceptualized and designed this study, performed the experiments and wrote the initial manuscript. JW, JH and PL conducted data analysis. GH performed data supervision and writing-review. All of the authors have read and approved the final manuscript.

Disclosure Statement

The authors report there are no competing interests to declare.

Ethics Statement

Animal Studies: Ethical approval has been obtained for animal experiments. (IACUC-AEWC-F2207018).

Data Availability Statement

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Additional information

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.