Microtubule-targeting anticancer drug eribulin induces drug efflux transporter P-glycoprotein

• Main Authors: Tomohiro Nabekura, Tatsuya Kawasaki, Misuzu Jimura, Koichi Mizuno, Yuichi Uwai
• Format: Article
• Language: English
• Published: Elsevier 2020-03-01
• Series: Biochemistry and Biophysics Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2405580819303024

This study examined the effects of microtubule-targeting anticancer drugs (paclitaxel, cabazitaxel, and eribulin) on the expression of drug efflux transporter P-glycoprotein, which is encoded by MDR1. Paclitaxel and eribulin induced MDR1 promoter activity in a concentration-dependent manner, while cabazitaxel had little effect in human intestinal epithelial LS174T cells. Overexpression of the nuclear receptor pregnane X receptor (PXR) gene (NR1I2) enhanced paclitaxel- and eribulin-induced MDR1 activation, but expression of the nuclear receptor co-repressor silencing mediator for retinoid and thyroid receptors (SMRT) gene (NCOR2) repressed MDR1 activation. Eribulin increased the mRNA and protein expression of P-glycoprotein in LS174T cells. Cellular uptake of rhodamine 123 and calcein-acetoxymethyl ester (calcein-AM), P-glycoprotein substrates, decreased in paclitaxel- or eribulin-treated LS174T cells. Eribulin also increased MDR1 promoter activity in human breast cancer MCF7 cells. The results suggest that the microtubule-targeting anticancer drug eribulin can induce the drug efflux transporter P-glycoprotein via PXR in human intestinal and breast cancer cells and thus influence the efficacy of anticancer drugs. Keywords: P-glycoprotein, Drug transporter, Induction, Eribulin mesylate, Drug–drug interaction