Combined 18F-FDG PET/CT imaging and a gastric orthotopic xenograft model in nude mice are used to evaluate the efficacy of glycolysis-targeted therapy.

As discovered by Warburg 80 years ago most malignant cells rely more on glycolysis than normal cells. The high rate of glycolysis provides faster ATP production and greater lactic acid for tumor proliferation and invasion, thus indicating a potential target in anticancer therapy. Our previous studies demonstrated that 3-bromopyruvate (3-BrPA) and sodium citrate (SCT) inhibited tumor cell proliferation in vitro. However, the underlying mechanisms still warrant further investigation. In the present study, we employed the human SGC-7901 gastric cancer cell line, built an orthotopic xenograft model in nude mice, examined the treatment response by 18F-FDG PET/CT and investigated the mechanisms of 3-BrPA and SCT in vivo. Our results demonstrated that glycolysis and tumor growth were inhibited by intraperitoneal injection of 3-BrPA and SCT, which were imaged using an 18F-FDG PET/CT scanner. In addition, apoptosis induced by 3-BrPA and SCT was initiated by the upregulation of Bax and downregulation of Bcl-2, which promote cytochrome c release and subsequently activate caspase-9 and -3, and ultimately execute mitochondria-mediated apoptosis. Furthermore, apoptosis was also modulated by the generation of ROS and inhibition of survivin. Accordingly, 3-BrPA and SCT can inhibit glycolysis and induce gastric cancer apoptosis through the mitochondrial caspase-dependent pathway.

3-bromopyruvate and sodium citrate target glycolysis, suppress survivin, and induce mitochondrial-mediated apoptosis in gastric cancer cells and inhibit gastric orthotopic transplantation tumor growth.

Glycolysis is the primary method utilized by cancer cells to produce the energy (adenosine triphosphate, ATP) required for cell proliferation. Therefore, inhibition of glycolysis may inhibit tumor growth. We previously found that both 3-bromopyruvate (3-BrPA) and sodium citrate (SCT) can inhibit glycolysis in vitro; however, the underlying inhibitory mechanisms remain unclear. In the present study, we used a human gastric cancer cell line (SGC-7901) and an orthotopic transplantation tumor model in nude mice to explore the specific mechanisms of 3-BrPA and SCT. We found that both 3-BrPA and SCT effectively suppressed cancer cell proliferation, arrested the cell cycle, induced apoptosis, and decreased the production of lactate and ATP. 3-BrPA significantly reduced the glycolytic enzyme hexokinase activity, while SCT selectively inhibited phosphofructokinase-1 activity. Furthermore, 3-BrPA and SCT upregulated the expression of pro-apoptotic proteins (Bax, cytochrome c, and cleaved caspase-3) and downregulated the expression of anti-apoptotic proteins (Bcl-2 and survivin). Finally, our animal model of gastric cancer indicated that intraperitoneal injection of 3-BrPA and SCT suppressed orthotopic transplantation tumor growth and induced tumor apoptosis. Taken together, these results suggest that 3-BrPA and SCT selectively suppress glycolytic enzymes, decrease ATP production, induce mitochondrial-mediated apoptosis, downregulate survivin, and inhibit tumor growth. Moreover, an intraperitoneal injection is an effective form of administration of 3-BrPA and SCT.