Sorafenib inhibits 5-fluorouracil-resistant gastric cancer cell growth

Abstract

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:

• Gastric cancer
• 5-fluorouracil
• sorafenib
• sphere formation
• drug resistance
• neoplastic stem cell

Acknowledgements

The authors would like to appreciate Chul Hoon Kim, Jeon Han Park, Hoguen Kim, and Yong Chan Lee as advisors of the doctoral thesis (Hee Man Kim), for their critical revision of the manuscript, and for their intellectual contributions.

Disclosure statement

The authors declare that they have no competing interests.

Additional information

Funding

This work was supported by Bayer Korea, Ltd [7-2009-0108] and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology [2011-0013944] (Jae Hee Cho).