RRC ID 31701
Author Xiang QF, Zhang DM, Wang JN, Zhang HW, Zheng ZY, Yu DC, Li YJ, Xu J, Chen YJ, Shang CZ.
Title Cabozantinib reverses multidrug resistance of human hepatoma HepG2/adr cells by modulating the function of P-glycoprotein.
Journal Liver Int
Abstract 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).
METHODS: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.
RESULTS: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.
CONCLUSION: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.
Volume 35(3)
Pages 1010-23
Published 2015-3-1
DOI 10.1111/liv.12524
PMID 24621440
MeSH ATP Binding Cassette Transporter, Subfamily B, Member 1 / drug effects* ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism Anilides / pharmacology Anilides / therapeutic use* Animals Carcinoma, Hepatocellular / drug therapy* Drug Resistance, Multiple / drug effects* Drug Resistance, Neoplasm / drug effects* Extracellular Signal-Regulated MAP Kinases / metabolism Female HEK293 Cells Hep G2 Cells Humans Liver Neoplasms / drug therapy* Mice, Inbred BALB C Mice, Nude Molecular Docking Simulation Proto-Oncogene Proteins c-akt / metabolism Proto-Oncogene Proteins c-met / metabolism Pyridines / pharmacology Pyridines / therapeutic use* Random Allocation Xenograft Model Antitumor Assays
IF 5.175
Times Cited 36
DNA material Human MDR1 cDNA (RDB01372)