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Journal of cellular biochemistry

P-Glycoprotein Inhibition Sensitizes Human Breast Cancer Cells to Proteasome Inhibitors.


PMID 27813130

Abstract

Although effective for the treatment of hematological malignancies, the FDA approved proteasome inhibitors bortezomib and carfilzomib have limited efficacy in solid tumors including triple negative breast cancer (TNBC). Chemotherapy is the only option for treating TNBC due to the absence of specific therapeutic targets. Therefore, development of new TNBC therapeutic strategies has been warranted. We studied whether P-glycoprotein (P-gp) inhibition could sensitize TNBC cells to proteasome inhibitors. When verapamil, a P-gp inhibitor, was combined with the proteasome inhibitor MG132, 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 IκBα and p27