ABSTRACT
Cabozantinib, mainly targeting cMet and vascular endothelial growth factor receptor 2, is the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the lower response rate and resistance limit its enduring clinical benefit. In this study, we found that cMet-low HCC cells showed primary resistance to cMet inhibitors, and the combination of cabozantinib and mammalian target of rapamycin (mTOR) inhibitor, rapamycin, exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells. Mechanically, the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT, extracellular signal-regulated protein kinases, mTOR, and common downstream signal molecules of receptor tyrosine kinases; decreased cyclin D1 expression; and induced cell cycle arrest. Meanwhile, rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition. These effects were further validated in xenograft models. In conclusion, our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.
Subject(s)
Animals , Humans , Anilides/pharmacology , Carcinoma, Hepatocellular/drug therapy , Cell Line, Tumor , Cell Proliferation , Endothelial Cells/metabolism , Liver Neoplasms/drug therapy , Pyridines/pharmacology , Sirolimus/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
<p><b>OBJECTIVE</b>To investigate pharmacokinetic parameters of peoniflorin, albiflorin and amygdaloside after administration of Guizhi Fuling capsule in beagle dogs.</p><p><b>METHOD</b>Plasma was collected from forelimb vein of Beagle dogs after oral administration of Guizhi Fuling capsule. HPLC-MS/MS method was used to determine the concentrations of constituents in plasma. The pharmacokinetic parameters were analyzed by program DAS 2.0.</p><p><b>RESULT</b>The limit of quantitation of peoniflorin, albiflorin and amygdaloside were 0.25, 2.64, 0.04 microg x L(-1), respectively. After administrated with different doses, half-life of peoniflorin in dogs were 4.33, 3.62 h, albiflorin were 6.16, 5.91 h, amygdaloside were 2.43, 1.32 h. The AUC(0-t) of all components were related to dose.</p><p><b>CONCLUSION</b>The pharmacokinetic course of peoniflorin, albiflorin and amygdaloside can be described by two-compartment model, and these components have high expose.</p>