Selinexor Improves the Anti-Cancer Effect of Tucidinostat on TP53 Wild-type Breast Cancer

Abstract

Background: Histone deacetylase (HDAC) is closely related to the occurrence and development of breast cancer (BC). Its inhibitor (HDACi) has been used to treat BC, while the efficacy of clinical trials was not reached expectations. HDACi combined with other drugs may be an effective strategy. This study explored the effect of HDACitucidinostat combined with selinexor, anexportin 1 (XPO1) inhibitor, on BC cellsin vitro. Methods: BC cell lines of MCF-7 (wt-TP53), MDA-MB-175 (wt-TP53), MDA-MB-134 (mut-TP53), T47D (mut-TP53) were cultured. The IC50 values of tucidinostat and selinexor on BC cells were calculated. The effects of tucidinostat and selinexor on proliferation, invasion and apoptosis of BC cells were observed accordingly. Western blotting was used to detect the protein expressions of p53, p21, Cyclin D1, Bcl-2 and Bax.Results:Compared with mut-TP53 BC, both tucidinostat and selinexor showed better inhibitory activitiesonwt-TP53 BC including MCF-7 and MDA-MB-175. Tucidinostat combined with selinexor significantly improved the effects of tucidinostat alone on the proliferation and invasion inhibitions and apoptosis promotionsof MCF-7 and MDA-MB-175 cells in vitro. It also significantly enhanced the effects of tucidinostat on up-regulating the expression levels of acetyl-p53, nuclear p53, total p53, p21 and Bax, and down-regulating the expression levels of Cyclin D1 and Bcl-2 in MCF-7 or MDA-MB-175 cells. Conclusion: Taken together, we believe that tucidinostat and selinexor are potentially effective drug combinations for the treatment of wt-TP53 BC, and the molecular mechanism may be throughenhancing the activity of p53 in the nucleus of BC cells to suppress proliferation and invasion and promote apoptosis of BC cells.