Enhanced antitumor efficacy by blocking activation of the phosphatidylinositol 3‐kinase/Akt pathway during anti‐angiogenesis therapy

Anti‐angiogenesis has been a promising strategy for cancer therapy. However, many signal pathways are activated during anti‐angiogenic treatment to counteract the therapeutic efficacy. Among these pathways, evidence has directly pointed to the phosphatidylinositol 3‐kinase/Akt (PI3K/Akt) pathway, whose activation resulted in tolerance to the absence of nutrients and oxygen when tumor angiogenesis has been inhibited. In the present study, we investigated the effects of blocking activation of the PI3K/Akt pathway on cell survival in vitro and tumor growth in vivo during anti‐angiogenesis therapy. In modeled microenvironments in vitro , we observed that the phosphorylation of Akt in tumor cells was increased gradually in the absence of serum and oxygen in a time‐dependent manner. The specific inhibitors of PI3K inhibited the proliferation of tumor cells in a dose‐dependent manner in vitro . Moreover, inhibition was enhanced gradually with increased serum deprivation and/or hypoxia. In a mouse tumor model, we found the phosphorylation of Akt obviously increased following anti‐angiogenic therapy using plasmids encoding soluble vascular endothelial growth factor receptor‐2, but significantly reduced after treatment with LY294002. Consequently, the combinational treatment exhibited better antitumor effects compared with single treatments, presenting larger necrosis‐like areas, more apoptotic cells, less microvessel density and less phosphorylated Akt in tumors. These results suggest that blocking activation of the PI3K/Akt pathway during anti‐angiogenesis therapy could enhance antitumor efficacy. Thus, targeting the PI3K/Akt pathway might be a promising strategy to reverse tumor resistance to anti‐angiogenesis therapy. ( Cancer Sci 2011; 102: 1469–1475)