Both authors contributed equally to this work.
Cabozantinib reverses multidrug resistance of human hepatoma HepG2/adr cells by modulating the function of P-glycoprotein
Article first published online: 2 APR 2014
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Volume 35, Issue 3, pages 1010–1023, March 2015
How to Cite
Liver Int. 2015; 35: 1010–1023
- Issue published online: 11 FEB 2015
- Article first published online: 2 APR 2014
- Accepted manuscript online: 12 MAR 2014 10:29AM EST
- Manuscript Accepted: 5 MAR 2014
- Manuscript Received: 14 OCT 2013
- National Natural Science Foundation of China. Grant Numbers: 81372562, 81070453
- National Natural Science Foundation for Young Scientists of China. Grant Number: 31200736
- hepatocellular carcinoma;
- multidrug resistance;
Background & Aims
Cabozantinib, a small-molecule multitargeted tyrosine kinase inhibitor, has entered into a phase III clinical trial for the treatment of hepatocellular carcinoma (HCC). This study assessed the mechanistic effect of cabozantinib on the reversal of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR).
CCK-8 assays and tumour xenografts were used to investigate the reversal of MDR in vitro and in vivo respectively. Substrate retention assays were evaluated by fluorescence microscope and flow cytometry. Western blotting was used to detect protein expression levels. mRNA expression was determined by qPCR. The ATPase activity of P-gp was investigated using Pgp-Glo™ assay systems. The binding mechanism of cabozantinib to P-gp at the molecular level was evaluated using docking analysis.
Cabozantinib enhanced the cytotoxicity of P-gp substrate drugs in HepG2/adr and HEK293-MDR1 cells but had no effect on non-P-gp substrates. In addition, cabozantinib increased the accumulation of P-gp substrates in HepG2/adr cells but had no effect in HepG2 cells. Furthermore, cabozantinib did not alter the expression of P-gp mRNA or protein but did stimulate the activity of P-gp ATPase. The docking study indicated that cabozantinib and verapamil may partially share a binding site on P-gp. The reversal concentrations of cabozantinib did not affect the expression of MET, AKT and ERK1/2. Significantly, cabozantinib increased the inhibitory efficacy of doxorubicin in P-gp-overexpressing HepG2/adr cell xenografts in nude mice.
Cabozantinib reverses P-gp-mediated MDR by directly inhibiting the efflux function of P-gp, indicating that cabozantinib may help to reverse P-gp-mediated MDR in HCC and other cancer chemotherapy.