Ibulocydine inhibits migration and invasion of TNBC cells via MMP-9 regulation

Abstract

Background Triple-negative breast cancer (TNBC) accounts for approximately 15–20% of all breast cancer types, indicating poor survival prognosis with more aggressive biology of rapidly progressive growth, metastasis to the lung, and short response duration to available therapies. TNBC is characterized by the negative expression of three hormone receptors. Therefore, compared to other breast cancers, TNBC is difficult to treat using hormone inhibitors and is resistant to chemotherapy. Additionally, the lack of effective targets limits the development of therapeutics. Ibulocydine (IB) is a novel (cyclin-dependent kinase) CDK7/9 inhibitor prodrug displaying potent anti-cancer effects against various cancer cell types. We performed the following experiments to determine whether IB inhibits metastasis and eventually overcomes the poor drug response in TNBC. Methods Colony-forming, cell counting kit-8 (CCK-8), wound healing, trans-well assays, and western blotting were performed in vitro. An experimental metastasis model was developed via intravenous injection of MDA-MB-231-Luc cells in vivo, and tumor growth was monitored using an In Vivo Imaging System (IVIS) spectrum. Results The result showed that IB reduced the viability of various TNBC cell lines in a dose-dependent manner. Pretreatment with z-VAD effectively blocked IB-induced cell death and cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP) in TNBC cells. A reduction in the migration and invasion abilities of TNBC cell lines was observed following IB treatment in migration and invasion assays. We determined the expression levels of metastasis-related markers using western blotting and found that the expression of matrix metalloproteinase-9 (MMP-9) decreased in an IB dose-dependent manner. In addition, IB-induced inhibition of migration and invasion was blocked in MMP9-overexpressing MDA-MB-231-Luc cells. Results of in vivo experiments using the metastasis model showed that metastasis of MDA-MB-231-Luc cells to the lung was inhibited by IB. Conclusions Collectively, these results showed that IB inhibited the growth of TNBC cells by inducing caspase-mediated apoptosis and blocking metastasis by reducing MMP-9 expression, suggesting a novel therapeutic agent for metastatic TNBC.