14032 Background: Colorectal cancer is the leading cause of cancer deaths in the USA, largely due to metastatic disease in the liver. The specific activity of the non-receptor protein tyrosine kinase, Src, is increased during colon tumor progression and contributes to metastasis; thus, Src inhibitors may have efficacy in the treatment of advanced-stage colon cancer. AZD0530 is a potent, orally available Src/Abl kinase inhibitor currently in clinical trials. Methods: We examined the effects of AZD0530 alone and in combination with oxaliplatin on two colon tumor cell lines, KM12L4 and LS174T in vitro and in orthotopic nude mouse models. AZD0530 inhibits in vitro proliferation and cellular migration of KM12L4 and LS174T, and decreases phosphorylation of the Src substrates FAK and paxillin in a dose- dependent manner. To examine the ability of AZD0530 to affect colon cancer growth and metastasis in a nude mouse model, we inoculated 1x106 cells into the cecum of nude mice. After 2 weeks, mice were treated with vehicle (n=12), AZD0530 alone (n=13; 25mg/kg/day by oral gavage), oxaliplatin alone (n=13; 5mg/kg/day twice weekly), or AZD0530 and oxaliplatin (n=13). Mice were sacrificed after 4 weeks of treatment. Results: Tumor incidence in all groups of mice was greater than 80%. Mice treated with AZD0530 had an average cecal tumor weight of 0.26 g compared with 0.32 g for control (P=0.24). In contrast, the incidence of liver metastases was reduced by 50% in mice treated with AZD0530 alone or oxaliplatin alone, and no mice developed pathologically evident liver metastases when the combination of inhibitors was used. Furthermore, in mice that developed liver metastases, AZD0530 decreased the size of these metastases 9-fold compared with control. Immunohistochemical analysis of primary cecal tumors demonstrated a decrease in phosphorylated Src (Y418) and FAK (Y861) in AZD0530-treated mice compared with control. Conclusions: These results support further investigation of AZD0530, both alone and in combination, as a new therapeutic strategy for the treatment of advanced colon cancer. No significant financial relationships to disclose.
The Akt Inhibitor ISC-4 Activates Prostate Apoptosis Response Protein-4 and Reduces Colon Tumor Growth in a Nude Mouse Model