Proteasome Inhibition As A Potential Anti Breast Cancer Therapy

When verapamil, a L-type calcium channel blocker with P-glycoprotein (P-gp) and CYP3A4 inhibitory properties, is combined with MG132 or bortezomib or carfilzomib, the cytotoxic effects and apoptosis in TNBC MDA-MB-231 cells were enhanced, compared to each treatment alone. Furthermore, addition of verapamil improved proteasome-inhibitory properties of MG132, bortezomib or carfilzomib in MDA-MB-231 cells, as shown by the increased accumulation of ubiquitinated proteins and proteasome substrates such as I0ðB0ł and p27kip1. Additionally, when nicardipine, another P-gp inhibitor, was combined with bortezomib or carfilzomib, enhanced inhibition of MDA-MB-231 cell proliferation was observed. These findings indicate that P-gp inhibitors could sensitize TNBC cells to structurally and functionally diverse proteasome inhibitors and might provide new treatment strategy for TNBC. Taken together, the studies presented in this dissertation will help to identify additional targets for proteasome inhibitors as well as their crosstalk and might help in designing new combination treatments for difficult to treat solid tumors like TNBC.