Src is a non-receptor tyrosine kinase involved in the crosstalk and mediation of many signaling pathways that promote cell proliferation, adhesion, invasion, migration and tumorigenesis. Increased Src activity has been reported in many types of human cancer including gastric cancer. Therefore, this factor has been identified as a promising therapeutic target for cancer treatments, and targeting Src in gastric cancer is predicted to have potent effects. We evaluated the antitumor effect of a c-Src/Abl kinase inhibitor saracatinib (AZD0530) alone or combined with chemotherapeutic agents in gastric cancer cell lines and a NCI-N87 xenograft model. Among 10 gastric cancer cell lines, saracatinib specifically inhibited the growth and migration/invasion of SNU216 and NCI-N87 cells. Saracatinib blocked the Src/FAK, HER family and oncogenic signaling pathways, and it induced G1 arrest and apoptosis in SNU216 and NCI-N87 cells. Apoptosis required induction of the pro-apoptotic BCL2 family member, Bim. Knockdown of Bim using siRNA decreased apoptosis induced by treatment with saracatinib, suggesting that Bim has an important role in saracatinib-induced apoptosis. Saracatinib enhanced the effects of lapatinib, an EGFR/HER2 dual inhibitor, in SNU216 and NCI-N87 cells. Furthermore, combined treatment with saracatinib and 5-FU or cisplatin exerted synergistic effects in both saracatinib-sensitive and saracatinib-resistant cells. Consistent with our in vitro findings, co-treatment with saracatinib and 5-FU resulted in enhanced antitumor activity in the NCI-N87 xenografts. These data indicate that the inhibition of Src kinase activity by saracatinib alone or in combination with other agents can be one of strategies to target gastric cancer.
- Received February 3, 2012.
- Revision received September 25, 2012.
- Accepted November 2, 2012.
- Copyright © 2012, American Association for Cancer Research.