title: 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.
abstract: 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.
authors.affiliation: Department of Gastrointestinal and Gland Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.
authors.forename: Ting-An
authors.initials: TA
authors.lastname: Wang
authors.affiliation: Department of Gastrointestinal and Gland Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: Department of Gastrointestinal and Gland Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.
authors.forename: Xing-Yu
authors.initials: XY
authors.lastname: Guo
authors.affiliation: Department of Gastrointestinal and Gland Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.
authors.forename: Shu-Lin
authors.initials: SL
authors.lastname: Xian
authors.affiliation: Department of Gastrointestinal and Gland Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Lu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002951:Citrates / Q000008:administration & dosage*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007274:Injections, Intraperitoneal; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D011773:Pyruvates / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077559:Sodium Citrate; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays
chemical_list: C107489:BIRC5 protein, human; D002951:Citrates; D051034:Inhibitor of Apoptosis Proteins; D011773:Pyruvates; D017382:Reactive Oxygen Species; D000077022:Survivin; D000077559:Sodium Citrate; C017092:bromopyruvate; D000255:Adenosine Triphosphate