Endostar, a Modified Endostatin Induces Vascular Normalization to Improve Chemotherapy Efficacy Through Suppression of Src Signaling Pathway

Pathological angiogenesis can be a significant barrier to effective cancer therapy. Recent evidence suggests that Endostar may induce vascular normalization, thereby improving tumor perfusion and systemic chemotherapy. However, the molecular mechanism by which Endostar makes chemotherapy more effective remains to be fully elucidated. In this study, established 4T1 breast tumor-bearing animals treated with Endostar were evaluated at serial time points for treatment-associated changes in vascular architecture. As a result, Endostar induced a morphologically and functionally normalized vascular network. Combined Endostar and doxorubicin exhibited significant antitumor (34% of control size) and antimetastatic effects (29% of control metastatic nodules) in vivo. Finally, a two-dimensional gel electrophoresis and MALDIQ-TOF MS/MS-based proteomics approach was used to identify differentially expressed proteins involved in vascular normalization during Endostar administration. SRCIN1 was detected as one of the most significantly increased proteins. SRCIN1 is a novel Src-binding protein that regulates Src activation through C-terminal Src kinase, and attenuated Src activation during Endostar treatment was further confirmed by immunoblotting. Collectively, these data provided a molecular basis for vascular normalization, which were associated with the observed synergistic effect in vivo.