Elevated BCRP Transporter and Altered NF-кB Pathway Mediate Zoledronic Acid Resistance in MCF-7 Cells

Zoledronic acid (ZA), a bisphosphonate derivate, became the standard for preserving bone structure in cancer. Using various intracellular signaling pathways, including NF-κB, ZA inhibits tumor cell proliferation, induces apoptosis, and has additive and synergistic effects with cytotoxic agents. However, it has been observed that resistance has developed against ZA. This study aims to explore the underlying mechanisms of ZA resistance in MCF-7 breast cancer cells by investigating the activity and localization of the human breast cancer resistance protein (BCRP), changes in the NF-κB pathway, and the markers of epithelial-mesenchymal transition (EMT). Previously, MCF-7 cells were stepwise selected in increasing concentrations of ZA and became resistant to 8 µM ZA (MCF-7/Zol). We determined that BCRP levels were elevated with altered intracellular localization in ZA resistant MCF-7 cells, and BCRP pump caused a decrease in the substrate accumulation in the MCF-7/Zol cells whereas no change in intercellular substrate accumulation was observed in parental cells. MCF-7/Zol cells have increased amount of phosphorylated IκB which is associated with increased nuclear translocation of NF-κB. Concordantly, BCRP upregulation may be associated with increased nuclear NF-κB in ZA resistant cells. MCF-7/Zol cells did not harbor EMT markers. Elucidation of molecular mechanisms of resistance developed against chemotherapeutic agents is important to target critical pathways and proteins to eliminate the resistant clones as well as for determining biomarkers for MDR.