P-Glycoprotein Inhibition Sensitizes Human Breast Cancer Cells to Proteasome Inhibitors.
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 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. J. Cell. Biochem. 118: 1239-1248, 2017. © 2016 Wiley Periodicals, Inc.
Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan.|School of Pharmacy, Lake Erie College of Osteopathic Medicine, Bradenton, Florida, 34211.
Rahul R
RR
Deshmukh
Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.|Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, 48201-2013.
Seongho
S
Kim
Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, 48201-2013.
Yasmine
Y
Elghoul
Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan.|Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.|Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, 48201-2013.|Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan.
Q Ping
QP
Dou
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D054875:Ubiquitination; D014700:Verapamil / Q000494:pharmacology*
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; C436291:CDKN1B protein, human; C000606204:NFKBIA protein, human; D061988:Proteasome Inhibitors; D000072000:NF-KappaB Inhibitor alpha; D050760:Cyclin-Dependent Kinase Inhibitor p27; D014700:Verapamil
BORTEZOMIB; CARFILZOMIB; COMBINATION THERAPY; NICARDIPINE; P-GP INHIBITORS; PROTEASOME INHIBITORS; TRIPLE NEGATIVE BREAST CANCER; VERAPAMIL