Department of Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, PR China.
Oncol Rep. 2013 Jan;29(1):329-34. doi: 10.3892/or.2012.2085. Epub 2012 Oct 17.
Unrestrained glycolysis characterizes energy meta-bolism in cancer cells. Thus, antiglycolytic reagents such as 2-deoxy-D-glucose (2-DG) and 3-bromopyruvate (3-BrPA) may be used as anticancer drugs. In the present study, we examined the anticancer effects of 2-DG and 3-BrPA in pancreatic cancer cells and investigated whether these effects were regulated by hypoxia-inducible factor-1α (HIF-1α). To this end, 2-DG and 3-BrPA were administered to wild-type (wt) MiaPaCa2 and Panc-1 pancreatic cancer cells that were incubated under hypoxic (HIF-1α-positive) or normoxic (HIF-1α-negative) conditions. In addition, 2-DG and 3-BrPA were also administered to si-MiaPaCa2 and si-Panc-1 cells that lacked HIF-1α as a result of RNA interference. Following drug exposure, cell population was measured using a viability assay. Both HIF-1α-positive and HIF-1α-negative MiaPaCa2 cells were further studied for their expression of Cu/Zn-superoxide dismutase (SOD1) and poly(ADP-ribose) polymerase (PARP) and for their contents of ATP and fumarate. In the viability assay, either 2-DG or 3-BrPA decreased the tested cells. Concurrent use of 2-DG and 3-BrPA resulted in a greater decrease of cells and also facilitated ATP depletion. In addition, 3-BrPA was seen to both decrease SOD1 and increase fumarate, which suggests that the reagent impaired the mitochondria. 3-BrPA also decreased both full-length PARP and cleaved PARP, which suggests that 3-BrPA-induced decrease in cell population was a result of cell necrosis rather than apoptosis. When HIF-1α was induced in wt-MiaPaCa2 cells by hypoxia, some effects of 2-DG and 3-BrPA were attenuated. We conclude that: i) concurrent use of 2-DG and 3-BrPA has better anticancer effects in pancreatic cancer cells, ii) 3-BrPA impairs the mitochondria of pancreatic cancer cells and induces cell necrosis, and iii) HIF-1α regulates the anticancer effects of 2-DG and 3-BrPA in pancreatic cancer cells.
糖酵解不受控制是癌细胞能量代谢的特征。因此，诸如 2-脱氧-D-葡萄糖（2-DG）和 3-溴丙酮酸（3-BrPA）之类的抗糖酵解试剂可用作抗癌药物。在本研究中，我们检查了 2-DG 和 3-BrPA 在胰腺癌细胞中的抗癌作用，并研究了这些作用是否受缺氧诱导因子-1α（HIF-1α）的调节。为此，将 2-DG 和 3-BrPA 施用于在缺氧（HIF-1α 阳性）或常氧（HIF-1α 阴性）条件下孵育的野生型（wt）MiaPaCa2 和 Panc-1 胰腺癌细胞。此外，还将 2-DG 和 3-BrPA 施用于由于 RNA 干扰而缺乏 HIF-1α的 si-MiaPaCa2 和 si-Panc-1 细胞。暴露于药物后，通过活力测定法测量细胞群体。还进一步研究了 HIF-1α 阳性和 HIF-1α 阴性 MiaPaCa2 细胞的铜/锌超氧化物歧化酶（SOD1）和聚（ADP-核糖）聚合酶（PARP）的表达以及它们的 ATP 和富马酸含量。在活力测定中，2-DG 或 3-BrPA 降低了测试细胞。2-DG 和 3-BrPA 的联合使用导致细胞的更大减少，并且还促进了 ATP 的消耗。此外，观察到 3-BrPA 降低了 SOD1 并增加了富马酸，这表明该试剂损害了线粒体。3-BrPA 还降低了全长 PARP 和裂解的 PARP，这表明 3-BrPA 诱导的细胞群体减少是细胞坏死而不是细胞凋亡的结果。当缺氧诱导 wt-MiaPaCa2 细胞中的 HIF-1α 时，2-DG 和 3-BrPA 的某些作用被减弱。我们得出结论：i）在胰腺癌细胞中，2-DG 和 3-BrPA 的联合使用具有更好的抗癌作用，ii）3-BrPA 损害了胰腺癌细胞的线粒体并诱导了细胞坏死，以及 iii）HIF-1α 调节了 2-DG 和 3-BrPA 在胰腺癌细胞中的抗癌作用。
