Is targeting glycolysis with 2-deoxyglucose a viable therapeutic approach to bladder cancer?
Purpose: Although several therapeutic options for bladder cancer are available, the poor efficacy and palpable side effects are a major concern. Establishing a more effective intervention is urgently demanded. Glycolysis is considered a strategic target and has been often investigated in various cancers. Particularly, 2-deoxyglucose (2DG), a glycolysis inhibitor, has been intensely studied and shown to be encouraging and promising. Accordingly, we investigated how targeting glycolysis with 2DG would be effective on bladder cancer cells.
Methods: Bladder cancer 5637 cells were employed and cell viability was determined by MTT assay. To explore the anticancer mechanism of 2DG linked to glycolysis, two glycolytic parameters of hexokinase (HK) activity and ATP synthesis, metabolic signaling pathways, and induction of apoptosis were examined. Whether 2DG may potentiate several chemotherapeutic drugs being clinically used was also assessed for its possible chemosensitizing effect.
Results: A dose-dependent study of 2DG showed a 23-80% reduction in cell viability. HK activity and cellular ATP level were decreased by ~46% and ~56% with 2DG, respectively, indicating the glycolysis inhibition. AMP-activated protein kinase was activated while protein kinase B was inactivated and also mammalian target of rapamycin was inhibited with 2DG. These modulations would lead to the growth cessation and the cell viability reduction. In fact, the down-regulation of anti-apoptotic bcl-2 and the up-regulation of pro-apoptotic Bax in 2DG-treated cells indicated induction of apoptosis. Moreover, chemotherapeutic drugs with poor cytotoxic activity were selectively sensitized with 2DG, resulting in a significantly improved cell viability reduction.
Conclusion: 2DG has anticancer activity on bladder cancer cells and its anticancer mechanism involves the glycolysis inhibition, the modulations of certain signaling pathways, and induction of apoptosis. Additionally, 2DG has a chemosensitizing effect when combined with drugs. Thus, targeting glycolysis with 2DG appears to be an alternative, viable therapeutic approach to bladder cancer.
Kamat AM, Hahn NM, Efstathiou JA, et al. Bladder cancer. Lancet. 2016;388(10061): 2796-810.
Seigel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2015;65:5-29.
Shen Z, Shen T, Wientjes MG, et al. Intravesical treatments of bladder cancer: review. Pharm Res. 2008;25:1500-10.
Malmstrom PU. Intravesical therapy of superficial bladder cancer. Crit Rev Oncol Hematol. 2003;47:109-26.
Choi Y, Lee JH. The combination of tephrosin with 2-deoxy-D-glucose enhances the cytotoxicity via accelerating ATP depletion and blunting autophagy in human cancer cells. Cancer Biol Ther. 2011;12:989-96.
Warburg O. On the origin of cancer cells. Science. 1956;123:309-14.
Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4:891-9.
Pelicano H, Martin DS, Xu RH, et al. Glycolysis inhibition for anticancer treatment. Oncogene.
Xu RH, Pelicano H, Zhou Y, et al. Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res. 2005;65:613-21.
Zhong D, Xiong L, Liu T, et al. The glycolytic inhibition of 2-deoxyglucose activates multiple prosurvival pathways through IGF1R. J Biol Chem. 2009;284:23225-33.
Munoz-Pinedo C, Ruiz-Ruiz C, Ruiz de Almodovar C, et al. Inhibition of glucose metabolism sensitizes tumor cells to death receptor-triggered apoptosis through enhancement of death-inducing signaling complex formation and apical procaspase-8 processing. J Biol Chem. 2003;278:12759-68.
Wang L, Wang J, Xiong H, et al. Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP-53-deficiency-driven castration-resistant prostate cancer. EBioMedicine 2016;7:50-61.
Hernlund E, Strandberg Ihrlund L, Khan O, et al. Potentiation of chemotherapeutic drugs by energy metabolism inhibitors 2-deoxyglucose and etomoxir. Int J Cancer. 2008;123:476-83.
Hernlund E, Hjerpe E, Avall-Lundqvist E, et al. Ovarian carcinoma cells with low levels of β-F1-ATPase are sensitive to combined platinum and 2-deoxy-D-glucose treatment. Mol Cancer Ther. 2009;8:1916-23.
Coleman MC, Asbury CR, Daniels D, et al. 2-deoxy-D-glucose causes cytotoxicity, oxidative stress, and radiosensitization in pancreatic cancer. Free Radic Biol Med. 2008;44:322-31.
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. 2004;64:31-4.
Tagg SL, Foster PA, Leese MP, et al. 2-methoxyoestradiol-3,17-O,O-bis-sulpahamate and 2-deoxy-D-glucose in combination: a potential treatment for breast and prostate cancer. Br J Cancer. 2008;99:1842-8.
Mohanti BK, Rath GK, Anantha N, et al. Improving cancer radiotherapy with 2-deoxy-D-glucose: phase I/II clinical trials on human cerebral gliomas. Int J Radiati Oncol Biol Phys. 1996;35:103-11.
Miccoli L, Oudard S, Sureau F, et al. Intracellular pH governs the subcellular distribution of hexokinase in a glioma cell line. Biochem J. 1996;313:957-62.
Cheong JH, Park ES, Liang J, et al. Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models. Mol Cancer Ther. 2011;10:2350-62.
Priebe A, Tan L, Wahl H, et al. Glucose deprivation activates AMPK and induces cell death through modulation of Akt in ovarian cancer cells. Gynecol Oncol. 2011;122:389-95.
Lee YK, Park OJ. Regulation of mutual inhibitory activities between AMPK and Akt with quercetin in MCF-7 breast cancer cells. Oncol Rep. 2010;24:1493-7.
Bolster DR, Crozier SJ, Kimball SR, et al. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J Biol Chem. 2002;277:23977-80.
Lai E, Teodorp T, Volchuk A. Endoplasmic reticulum stress: signaling the unfolded protein response. Physiology. 2007;22:193-201.
Yip KW, Reed JC. Bcl-2 family proteins and cancer. Oncogene. 2008;27:6398-406.
Zhang HH, Guo XL. Combinational strategies of metformin and chemotherapy in cancers. Cancer Chemother Pharmacol. 2016;78:13-26.
Kuhajda FP. AMP-activated protein kinase and human cancer: cancer metabolism revisited. Int J Obes. 2008;32:S36-41.
MacFarlane M, Robinson GL, Cain K. Glucose – a sweet way to die: metabolic switching modulates tumor cell death. Cell Cycle. 2012;11:3919-25.
Landau BR, Lubs HA. Animal responses to 2-deoxy-D-glucose administration. Proc Soc Exp Biol Med. 1958;99:124-7.
Raez LE, Papadopoulos K, Ricart AD, et al. A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacolo. 2013;71:523-30.
Stein M, Lin H, Jeyamohan C, et al. Targeting tumor metabolism with 2-deoxyglucose in patients with castration-resistant prostate cancer and advanced malignancies. Prostate. 2010;70:1388-94.
This work is licensed under a Creative Commons Attribution 3.0 License.
International Journal of Cancer Therapy and Oncology (ISSN 2330-4049)
© International Journal of Cancer Therapy and Oncology (IJCTO)
To make sure that you can receive messages from us, please add the 'ijcto.org' domain to your e-mail 'safe list'. If you do not receive e-mail in your 'inbox', check your 'bulk mail' or 'junk mail' folders.