Separate and concurrent use of 2-deoxy-D-glucose and 3-bromopyruvate in pancreatic cancer cells

Xiao,Huijie; Li,Shasha; Zhang,Dapeng; Liu,Tongjun; Yu,Ming; Wang,Feng

doi:10.3892/or.2012.2085

Separate and concurrent use of 2-deoxy-D-glucose and 3-bromopyruvate in pancreatic cancer cells

Authors:
- Huijie Xiao
- Shasha Li
- Dapeng Zhang
- Tongjun Liu
- Ming Yu
- Feng Wang
View Affiliations

Affiliations: Department of Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China, Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China, Institute of Chinese and Modern Medicines for Acute Abdominal Diseases, Tianjin Medical University Nankai Hospital, Tianjin 300100, P.R. China, Department of Nutrition, Tianjin Medical University School of Public Health, Tianjin 300070, P.R. China
Published online on: October 17, 2012 https://doi.org/10.3892/or.2012.2085
Pages: 329-334

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Unrestrained glycolysis characterizes energy metabolism 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.

View Figures

View References

1	Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med. 285:1182–1186. 1971. View Article : Google Scholar : PubMed/NCBI
2	Koong AC, Mehta VK, Le QT, et al: Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys. 48:919–922. 2000. View Article : Google Scholar : PubMed/NCBI
3	Erler JT, Cawthorne CJ, Williams KJ, et al: Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and -independent mechanisms and contributes to drug resistance. Mol Cell Biol. 24:2875–2889. 2004. View Article : Google Scholar : PubMed/NCBI
4	Brown JM, Diehn M and Loo BW Jr: Stereotactic ablative radiotherapy should be combined with a hypoxic cell radiosensitizer. Int J Radiat Oncol Biol Phys. 78:323–327. 2010. View Article : Google Scholar : PubMed/NCBI
5	Warburg O: On the origin of cancer cells. Science. 123:309–314. 1956. View Article : Google Scholar : PubMed/NCBI
6	Zhong H, De Marzo AM, Laughner E, et al: Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 59:5830–5835. 1999.PubMed/NCBI
7	Semenza GL and Wang GL: A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 12:5447–5454. 1992.
8	Salceda S and Caro J: Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem. 272:22642–22647. 1997. View Article : Google Scholar
9	Fukuda R, Hirota K, Fan F, et al: Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J Biol Chem. 277:38205–38211. 2002. View Article : Google Scholar
10	Wang F, Li SS, Segersvärd R, et al: Hypoxia inducible factor-1 mediates effects of insulin on pancreatic cancer cells and disturbs host energy homeostasis. Am J Pathol. 170:469–477. 2007. View Article : Google Scholar : PubMed/NCBI
11	Natsuizaka M, Ozasa M, Darmanin S, et al: Synergistic up-regulation of Hexokinase-2, glucose transporters and angiogenic factors in pancreatic cancer cells by glucose deprivation and hypoxia. Exp Cell Res. 313:3337–3348. 2007. View Article : Google Scholar : PubMed/NCBI
12	Mathupala SP, Ko YH and Pedersen PL: Hexokinase-2 bound to mitochondria: cancer’s stygian link to the ‘Warburg Effect’ and a pivotal target for effective therapy. Semin Cancer Biol. 19:17–24. 2009.
13	Kirito K, Hu Y and Komatsu N: HIF-1 prevents the overproduction of mitochondrial ROS after cytokine stimulation through induction of PDK-1. Cell Cycle. 8:2844–2849. 2009. View Article : Google Scholar : PubMed/NCBI
14	Kurtoglu M, Maher JC and Lampidis TJ: Different toxic mechanisms of 2-deoxy-D-glucose versus 2-fluorodeoxy-D-glucose in hypoxic and normoxic tumor cells. Antioxid Redox Signal. 9:1383–1390. 2007. View Article : Google Scholar : PubMed/NCBI
15	Maher JC, Savaraj N, Priebe W, et al: Differential sensitivity to 2-deoxy-D-glucose between two pancreatic cell lines correlates with GLUT-1 expression. Pancreas. 30:e34–e39. 2005. View Article : Google Scholar : PubMed/NCBI
16	Wangpaichitr M, Savaraj N, Maher J, et al: Intrinsically lower AKT, mTOR and HIF activity correlates with increased sensitivity to 2-deoxy-D-glucose under hypoxia in lung cancer cell lines. Mol Cancer Ther. 7:1506–1513. 2008. View Article : Google Scholar : PubMed/NCBI
17	Maher JC, Wangpaichitr M, Savaraj N, et al: Hypoxia-inducible factor-1 confers resistance to the glycolytic inhibitor 2-deoxy-D-glucose. Mol Cancer Ther. 6:732–741. 2007. View Article : Google Scholar : PubMed/NCBI
18	Hernlund E, Ihrlund LS, Khan O, et al: Potentiation of chemotherapeutic drugs by energy metabolism inhibitors 2-deoxyglucose and etomoxir. Int J Cancer. 123:476–483. 2008. View Article : Google Scholar : PubMed/NCBI
19	Maschek G, Savaraj N, Priebe W, et al: 2-Deoxy-D-glucose increases the efficacy of adriamycin and paclitaxel in human osteosarcoma and non-small cell lung cancers in vivo. Cancer Res. 64:31–34. 2004. View Article : Google Scholar : PubMed/NCBI
20	Ko YH, Pedersen PL and Geschwind JF: Glucose catabolism in the rabbit VX2 tumor model for liver cancer: characterization and targeting hexokinase. Cancer Lett. 173:83–91. 2001. View Article : Google Scholar : PubMed/NCBI
21	Chen Z, Zhang H, Lu W and Huang P: Role of mitochondria-associated hexokinase II in cancer cell death induced by 3-bromopyruvate. Biochim Biophys Acta. 1787:553–560. 2009. View Article : Google Scholar : PubMed/NCBI
22	Kim JS, Ahn KJ, Kim JA, et al: Role of reactive oxygen species-mediated mitochondrial dysregulation in 3-bromopyruvate induced cell death in hepatoma cells: ROS-mediated cell death by 3-BrPA. J Bioenerg Biomembr. 40:607–618. 2008. View Article : Google Scholar : PubMed/NCBI
23	Hulleman E, Kazemier KM, Holleman A, et al: Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells. Blood. 113:2014–2021. 2009. View Article : Google Scholar : PubMed/NCBI
24	Ko YH, Smith BL, Wang Y, et al: Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem Biophys Res Commun. 324:269–275. 2004. View Article : Google Scholar : PubMed/NCBI
25	Pereira da Silva AP, El-Bacha T, Kyaw N, et al: Inhibition of energy-producing pathways of HepG2 cells by 3-bromopyruvate. Biochem J. 417:717–726. 2009.PubMed/NCBI
26	Greijer AE, van der Groep P, Kemming D, et al: Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). J Pathol. 206:291–304. 2005. View Article : Google Scholar : PubMed/NCBI
27	Indran IR, Tufo G, Pervaiz S and Brenner C: Recent advances in apoptosis, mitochondria and drug resistance in cancer cells. Biochim Biophys Acta. 1807:735–745. 2011. View Article : Google Scholar : PubMed/NCBI
28	Mangerich A and Bürkle A: How to kill tumor cells with inhibitors of poly(ADP-ribosyl)ation. Int J Cancer. 128:251–265. 2011. View Article : Google Scholar : PubMed/NCBI
29	Koivunen P, Hirsilä M, Remes AM, et al: Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J Biol Chem. 282:4524–4532. 2007. View Article : Google Scholar : PubMed/NCBI
30	Liang HL, Sedlic F, Bosnjak Z and Nilakantan V: SOD1 and MitoTEMPO partially prevent mitochondrial permeability transition pore opening, necrosis, and mitochondrial apoptosis after ATP depletion recovery. Free Radic Biol Med. 49:1550–1560. 2010. View Article : Google Scholar
31	Ha HC and Snyder SH: Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc Natl Acad Sci USA. 96:13978–13982. 1999. View Article : Google Scholar : PubMed/NCBI
32	Qin JZ, Xin H and Nickoloff BJ: 3-Bromopyruvate induces necrotic cell death in sensitive melanoma cell lines. Biochem Biophys Res Commun. 396:495–500. 2010. View Article : Google Scholar : PubMed/NCBI