Background: Sorafenib is a multi-kinase inhibitor used in the treatment of various cancers. This study investigated the inhibitory effect of sorafenib on xenograft models of gastric cancer cells and 5-fluorouracil (5-FU)-resistant cells.
Methods: The half-maximal inhibitory concentration (IC50) of sorafenib in NCI-N87 cells was determined. Xenograft models were established using BALB/c nude mice and were divided into four groups treated with vehicle, sorafenib (20 mg kg-1 day-1), 5-FU (50 mg kg-1 week-1), or a combination of sorafenib (20 mg kg-1 day-1) plus 5-FU (50 mg kg-1 week-1). 5-FU-resistant NCI-N87 cells were established by repeated exposure to 5-FU.
Results: Sorafenib inhibited NCI-N87 cell growth in a concentration-dependent manner with a mean IC50 of 16.345 ± 5.391 μM. Phosphorylation levels of mitogen-activated protein kinase kinase and extracellular signal-regulated kinase in these cells decreased in a dose-dependent manner after exposure to sorafenib. Sorafenib induced the activation of caspase-3, and its combination with 5-FU more effectively inhibited the growth of xenograft tumors than either sorafenib or 5-FU alone (p < 0.05). Sorafenib markedly inhibited 5-FU-resistant NCI-N87 cell growth as well as sphere formation in both parental and 5-FU-resistant NCI-N87 cells.
Conclusions: The sorafenib and 5-FU combination exhibited enhanced antitumor effects in a gastric cancer xenograft model and inhibited 5-FU-resistant cell proliferation and sphere formation. These findings suggest that sorafenib is useful in overcoming gastric cancer resistance to conventional chemotherapy.
Keywords: 5-fluorouracil; Gastric cancer; drug resistance; neoplastic stem cell; sorafenib; sphere formation.