Cancer Therapeutics Insights Colorectal Cancer Cells Refractory to Anti-VEGF Treatment Are Vulnerable to Glycolytic Blockade due to Persistent Impairment of Mitochondria

Antiangiogenesis therapy has shed new light on cancer treatment, but its effectiveness, especially for overall patient survival, is still controversial. Here, we show that antiangiogenesis treatment causes a persistent suppression of mitochondria biogenesis in colorectal cancer cells, which renders them more sensitive to glycolytic blockade therapy. We first analyzed bevacizumab-resistant colon cancer xenografts by twodimensional BlueNative/SDS-PAGEand founda serious andpersistent loss ofmitochondrial protein complex I. Furthermetabolic assays revealed significantly impairedmitochondrial function and hyperactive glycolysis, which were concomitant with the upregulation of HIF-1 and Hsp70. The treatment of bevacizumab-resistant cells with the glycolysis inhibitor 3-BrPA caused cell senescence in vitro. Intraperitoneal injection of 3-BrPA to xenograftmice bearing bevacizumab-resistant cells also resulted in smaller tumor volume and longer survival. These data provide direct evidence for the mitochondrial destruction of bevacizumab-resistant tumor cells and suggest that glycolysis blockade may potentiate the therapeutic effect of antiangiogenesis treatment. Mol Cancer Ther; 12(5); 717–24. 2013 AACR.