Anti-Glycolytic Drugs in the Treatment of Hepatocellular Carcinoma: Systemic and Locoregional Options
Abstract
1. Introduction
2. Warburg Effect
3. HCC Microenvironment and Adapting Mechanisms
4. Effect of Arterial Embolization on HCC Microenvironment
5. Targeting Glycolysis
6. Targeting Glucose Transporters
6.1. GLUT-1 Antibody
6.2. Ritonavir
6.3. BAY-876
6.4. Fasentin
6.5. Phloretin, Silybin, and Quercetin
6.6. Sodium-Glucose Linked Transporters
7. Targeting Enzymes Involved in Glycolysis
7.1. 2-Deoxy-D-Glucose (2-DG)
7.2. Dichloroacetate (DCA)
7.3. 3-Bromopyruvate (3-BrPA)
7.4. Bumetanide = (BU)
8. Discussion/Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Forner, A.; Llovet, J.M.; Bruix, J. Hepatocellular carcinoma. Lancet 2012, 379, 1245–1255. [Google Scholar] [CrossRef] [PubMed]
- Chevallier, O.; Zhao, K.; Marinelli, B.; Yarmohammadi, H. Image-guided percutaneous locoregional therapies for hepatocellular carcinoma. Chin. Clin. Oncol. 2023, 12, 17. [Google Scholar] [CrossRef]
- Brown, K.T.; Do, R.K.; Gonen, M.; Covey, A.M.; Getrajdman, G.I.; Sofocleous, C.T.; Jarnagin, W.R.; D’angelica, M.I.; Allen, P.J.; Erinjeri, J.P.; et al. Randomized Trial of Hepatic Artery Embolization for Hepatocellular Carcinoma Using Doxorubicin-Eluting Microspheres Compared with Embolization with Microspheres Alone. J. Clin. Oncol. 2016, 34, 2046–2053. [Google Scholar] [CrossRef] [PubMed]
- Qiao, W.; Wang, Q.; Hu, C.; Zhang, Y.; Li, J.; Sun, Y.; Yuan, C.; Wang, W.; Liu, B.; Zhang, Y. Interim efficacy and safety of PD-1 inhibitors in preventing recurrence of hepatocellular carcinoma after interventional therapy. Front. Immunol. 2022, 13, 1019772. [Google Scholar] [CrossRef] [PubMed]
- El-Gazzaz, G.; Sourianarayanane, A.; Menon, K.N.; Sanabria, J.; Hashimoto, K.; Quintini, C.; Kelly, D.; Eghtesad, B.; Miller, C.; Fung, J.; et al. Radiologic-histological correlation of hepatocellular carcinoma treated via pre-liver transplant locoregional therapies. Hepatobiliary Pancreat. Dis. Int. 2013, 12, 34–41. [Google Scholar] [CrossRef] [PubMed]
- Warburg, O. On the Origin of Cancer Cells. Science 1956, 123, 309–314. [Google Scholar] [CrossRef]
- Anastasiou, D. Tumour microenvironment factors shaping the cancer metabolism landscape. Br. J. Cancer 2017, 116, 277–286. [Google Scholar] [CrossRef]
- Vanhove, K.; Graulus, G.-J.; Mesotten, L.; Thomeer, M.; Derveaux, E.; Noben, J.-P.; Guedens, W.; Adriaensens, P. The Metabolic Landscape of Lung Cancer: New Insights in a Disturbed Glucose Metabolism. Front. Oncol. 2019, 9, 1215. [Google Scholar] [CrossRef]
- Ganapathy-Kanniappan, S.; Geschwind, J.F. Tumor glycolysis as a target for cancer therapy: Progress and prospects. Mol. Cancer. 2013, 12, 152. [Google Scholar] [CrossRef]
- Wu, X.-Z.; Xie, G.-R.; Chen, D. Hypoxia and hepatocellular carcinoma: The therapeutic target for hepatocellular carcinoma. J. Gastroenterol. Hepatol. 2007, 22, 1178–1182. [Google Scholar] [CrossRef]
- Brogi, E.; Schatteman, G.; Wu, T.; Kim, E.A.; Varticovski, L.; Keyt, B.; Isner, J.M. Hypoxia-induced paracrine regulation of vascular endothelial growth factor receptor expression. J. Clin. Investig. 1996, 97, 469–476. [Google Scholar] [CrossRef]
- Kuroki, M.; Voest, E.E.; Amano, S.; Beerepoot, L.V.; Takashima, S.; Tolentino, M.; Kim, R.Y.; Rohan, R.M.; Colby, K.A.; Yeo, K.T.; et al. Reactive oxygen intermediates increase vascular endothelial growth factor expression in vitro and in vivo. J. Clin. Investig. 1996, 98, 1667–1675. [Google Scholar] [CrossRef]
- Weljie, A.M.; Jirik, F.R. Hypoxia-induced metabolic shifts in cancer cells: Moving beyond the Warburg effect. Int. J. Biochem. Cell Biol. 2011, 43, 981–989. [Google Scholar] [CrossRef]
- Kakudo, N.; Morimoto, N.; Ogawa, T.; Taketani, S.; Kusumoto, K. Hypoxia Enhances Proliferation of Human Adipose-Derived Stem Cells via HIF-1ɑ Activation. PLoS ONE 2015, 10, e0139890. [Google Scholar] [CrossRef]
- Chen, Y.-J.; Mahieu, N.G.; Huang, X.; Singh, M.; Crawford, P.; Johnson, S.L.; Gross, R.W.; Schaefer, J.; Patti, G.J. Lactate metabolism is associated with mammalian mitochondria. Nat. Chem. Biol. 2016, 12, 937–943. [Google Scholar] [CrossRef]
- Schlageter, M.; Terracciano, L.M.; D’angelo, S.; Sorrentino, P. Histopathology of hepatocellular carcinoma. World J. Gastroenterol. 2014, 20, 15955–15964. [Google Scholar] [CrossRef]
- Trojan, J.; Schroeder, O.; Raedle, J.; Baum, R.P.; Herrmann, G.; Jacobi, V.; Zeuzem, S. Fluorine-18 FDG positron emission tomography for imaging of hepatocellular carcinoma. Am. J. Gastroenterol. 1999, 94, 3314–3319. [Google Scholar] [CrossRef]
- Pirisi, M.; Avellini, C.; Fabris, C.; Scott, C.; Bardus, P.; Soardo, G.; Beltrami, C.A.; Bartoli, E. Portal vein thrombosis in hepatocellular carcinoma: Age and sex distribution in an autopsy study. J. Cancer Res. Clin. Oncol. 1998, 124, 397–400. [Google Scholar] [CrossRef]
- Tamura, S.; Kato, T.; Berho, M.; Misiakos, E.P.; O’Brien, C.; Reddy, K.R.; Nery, J.R.; Burke, G.W.; Schiff, E.R.; Miller, J.; et al. Impact of histological grade of hepatocellular carcinoma on the outcome of liver transplantation. Arch. Surg. 2001, 136, 25–30, discussion 31. [Google Scholar] [CrossRef] [PubMed]
- Mise, K.; Tashiro, S.; Yogita, S.; Wada, D.; Harada, M.; Fukuda, Y.; Miyake, H.; Isikawa, M.; Izumi, K.; Sano, N. Assessment of the biological malignancy of hepatocellular carcinoma: Relationship to clinicopathological factors and prognosis. Clin. Cancer Res. 1998, 4, 1475–1482. [Google Scholar]
- Gade, T.P.F.; Tucker, E.; Nakazawa, M.S.; Hunt, S.J.; Wong, W.; Krock, B.; Weber, C.N.; Nadolski, G.J.; Clark, T.W.I.; Soulen, M.C.; et al. Ischemia Induces Quiescence and Autophagy Dependence in Hepatocellular Carcinoma. Radiology 2017, 283, 702–710. [Google Scholar] [CrossRef] [PubMed]
- Jang, M.; Kim, S.S.; Lee, J. Cancer cell metabolism: Implications for therapeutic targets. Exp. Mol. Med. 2013, 45, e45. [Google Scholar] [CrossRef] [PubMed]
- Savic, L.J.; Chapiro, J.; Duwe, G.; Geschwind, J.F. Targeting glucose metabolism in cancer: New class of agents for loco-regional and systemic therapy of liver cancer and beyond? Hepatic Oncol. 2016, 3, 19–28. [Google Scholar] [CrossRef] [PubMed]
- Rastogi, S.; Banerjee, S.; Chellappan, S.; Simon, G.R. Glut-1 antibodies induce growth arrest and apoptosis in human cancer cell lines. Cancer Lett. 2007, 257, 244–251. [Google Scholar] [CrossRef]
- Dalva-Aydemir, S.; Bajpai, R.; Martinez, M.; Adekola, K.U.; Kandela, I.; Wei, C.; Singhal, S.; Koblinski, J.E.; Raje, N.S.; Rosen, S.T.; et al. Targeting the Metabolic Plasticity of Multiple Myeloma with FDA-Approved Ritonavir and Metformin. Clin. Cancer Res. 2015, 21, 1161–1171. [Google Scholar] [CrossRef]
- Yang, H.; Zhang, M.-Z.; Sun, H.-W.; Chai, Y.-T.; Li, X.; Jiang, Q.; Hou, J. A Novel Microcrystalline BAY-876 Formulation Achieves Long-Acting Antitumor Activity Against Aerobic Glycolysis and Proliferation of Hepatocellular Carcinoma. Front. Oncol. 2021, 11, 783194. [Google Scholar] [CrossRef]
- Wu, C.H.; Ho, Y.S.; Tsai, C.Y.; Wang, Y.J.; Tseng, H.; Wei, P.L.; Lee, C.H.; Liu, R.S.; Lin, S.Y. In vitro and in vivo study of phloretin-induced apoptosis in human liver cancer cells involving inhibition of type II glucose transporter. Int. J. Cancer 2009, 124, 2210–2219. [Google Scholar] [CrossRef]
- Yang, K.-C.; Tsai, C.-Y.; Wang, Y.-J.; Wei, P.-L.; Lee, C.-H.; Chen, J.-H.; Wu, C.-H.; Ho, Y.-S. Apple polyphenol phloretin potentiates the anticancer actions of paclitaxel through induction of apoptosis in human hep G2 cells. Mol. Carcinog. 2008, 48, 420–431. [Google Scholar] [CrossRef]
- Zhan, T.; Digel, M.; Küch, E.-M.; Stremmel, W.; Füllekrug, J. Silybin and dehydrosilybin decrease glucose uptake by inhibiting GLUT proteins. J. Cell. Biochem. 2010, 112, 849–859. [Google Scholar] [CrossRef]
- Brito, A.F.; Ribeiro, M.; Abrantes, A.M.; Mamede, A.C.; Laranjo, M.; Casalta-Lopes, J.E.; Gonçalves, A.C.; Ribeiro, A.B.S.; Tralhão, J.G.; Botelho, M.F. New Approach for Treatment of Primary Liver Tumors: The Role of Quercetin. Nutr. Cancer 2016, 68, 250–266. [Google Scholar] [CrossRef]
- Kaji, K.; Nishimura, N.; Seki, K.; Sato, S.; Saikawa, S.; Nakanishi, K.; Furukawa, M.; Kawaratani, H.; Kitade, M.; Moriya, K.; et al. Sodium glucose cotransporter 2 inhibitor canagliflozin attenuates liver cancer cell growth and angiogenic activity by inhibiting glucose uptake. Int. J. Cancer 2017, 142, 1712–1722. [Google Scholar] [CrossRef]
- Zhang, D.; Li, J.; Wang, F.; Hu, J.; Wang, S.; Sun, Y. 2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy. Cancer Lett. 2014, 355, 176–183. [Google Scholar] [CrossRef]
- Song, H.-J.; Cheng, J.-Y.; Hu, S.-L.; Zhang, G.-Y.; Fu, Y.; Zhang, Y.-J. Value of 18F-FDG PET/CT in detecting viable tumour and predicting prognosis of hepatocellular carcinoma after TACE. Clin. Radiol. 2015, 70, 128–137. [Google Scholar] [CrossRef]
- Raez, L.E.; Papadopoulos, K.; Ricart, A.D.; Chiorean, E.G.; DiPaola, R.S.; Stein, M.N.; Rocha Lima, C.M.; Schlesselman, J.J.; Tolba, K.; Langmuir, V.K.; 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. Pharmacol. 2013, 71, 523–530. [Google Scholar] [CrossRef]
- Dwarakanath, B.S.; Singh, D.; Banerji, A.K.; Sarin, R.; Venkataramana, N.K.; Jalali, R.; Vishwanath, P.N.; Mohanti, B.K.; Tripathi, R.P.; Kalia, V.K.; et al. Clinical studies for improving radiotherapy with 2-deoxy-D-glucose: Present status and future prospects. J. Cancer Res. Ther. 2009, 5 (Suppl. S1), S21–S26. [Google Scholar] [CrossRef]
- Aghaee, F.; Islamian, J.P.; Baradaran, B. Enhanced Radiosensitivity and Chemosensitivity of Breast Cancer Cells by 2-Deoxy-D-Glucose in Combination Therapy. J. Breast Cancer 2012, 15, 141–147. [Google Scholar] [CrossRef]
- Bonnet, S.; Archer, S.L.; Allalunis-Turner, J.; Haromy, A.; Beaulieu, C.; Thompson, R.; Lee, C.T.; Lopaschuk, G.D.; Puttagunta, L.; Bonnet, S.; et al. A Mitochondria-K+ Channel Axis Is Suppressed in Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth. Cancer Cell 2007, 11, 37–51. [Google Scholar] [CrossRef]
- Cao, W.; Yacoub, S.; Shiverick, K.T.; Namiki, K.; Sakai, Y.; Porvasnik, S.; Urbanek, C.; Rosser, C.J. Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation. Prostate 2008, 68, 1223–1231. [Google Scholar] [CrossRef]
- Flavin, D. Medullary thyroid carcinoma relapse reversed with dichloroacetate: A case report. Oncol. Lett. 2010, 1, 889–891. [Google Scholar] [CrossRef]
- Sanchez, W.Y.; McGee, S.; Connor, T.; Mottram, B.; Wilkinson, A.; Whitehead, J.; Vuckovic, S.; Catley, L. Dichloroacetate inhibits aerobic glycolysis in multiple myeloma cells and increases sensitivity to bortezomib. Br. J. Cancer 2013, 108, 1624–1633. [Google Scholar] [CrossRef]
- Sun, R.C.; Fadia, M.; Dahlstrom, J.E.; Parish, C.R.; Board, P.G.; Blackburn, A.C. Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res. Treat. 2010, 120, 253–260. [Google Scholar] [CrossRef]
- Wong, J.Y.; Huggins, G.S.; Debidda, M.; Munshi, N.C.; De Vivo, I. Dichloroacetate induces apoptosis in endometrial cancer cells. Gynecol. Oncol. 2008, 109, 394–402. [Google Scholar] [CrossRef] [PubMed]
- Zhou, Y.; Yi, X.; Stoffer, J.B.; Bonafe, N.; Gilmore-Hebert, M.; McAlpine, J.; Chambers, S.K. The Multifunctional Protein Glyceraldehyde-3-Phosphate Dehydrogenase Is Both Regulated and Controls Colony-Stimulating Factor-1 Messenger RNA Stability in Ovarian Cancer. Mol. Cancer Res. 2008, 6, 1375–1384. [Google Scholar] [CrossRef] [PubMed]
- Wintzell, M.; Löfstedt, L.; Johansson, J.; Pedersen, A.B.; Fuxe, J.; Shoshan, M. Repeated cisplatin treatment can lead to a multiresistant tumor cell population with stem cell features and sensitivity to 3-bromopyruvate. Cancer Biol. Ther. 2012, 13, 1454–1462. [Google Scholar] [CrossRef] [PubMed]
- Yarmohammadi, H.; Wilkins, L.R.; Erinjeri, J.P.; Novak, R.D.; Exner, A.; Wu, H.; Petre, E.N.; Boas, E.; Ziv, E.; Haaga, J.R. Efficiency of combined blocking of aerobic and glycolytic metabolism pathways in treatment of N1-S1 hepatocellular carcinoma in a rat model. J. Cancer Res. Ther. 2017, 13, 533–537. [Google Scholar]
- Macheda, M.L.; Rogers, S.; Best, J.D. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J. Cell. Physiol. 2004, 202, 654–662. [Google Scholar] [CrossRef]
- Liu, Y.; Cao, Y.; Zhang, W.; Bergmeier, S.; Qian, Y.; Akbar, H.; Colvin, R.; Ding, J.; Tong, L.; Wu, S.; et al. A Small-Molecule Inhibitor of Glucose Transporter 1 Downregulates Glycolysis, Induces Cell-Cycle Arrest, and Inhibits Cancer Cell Growth In Vitro and In Vivo. Mol. Cancer Ther. 2012, 11, 1672–1682. [Google Scholar] [CrossRef]
- Brown, R.S.; Wahl, R.L. Overexpression of Glut-1 glucose transporter in human breast cancer. An immunohistochemical study. Cancer 1993, 72, 2979–2985. [Google Scholar] [CrossRef]
- Siebeneicher, H.; Cleve, A.; Rehwinkel, H.; Neuhaus, R.; Heisler, I.; Müller, T.; Bauser, M.; Buchmann, B. Identification and Optimization of the First Highly Selective GLUT1 Inhibitor BAY-876. ChemMedChem 2016, 11, 2261–2271. [Google Scholar] [CrossRef]
- Tarao, K.; Nozaki, A.; Ikeda, T.; Sato, A.; Komatsu, H.; Komatsu, T.; Taguri, M.; Tanaka, K. Real impact of liver cirrhosis on the development of hepatocellular carcinoma in various liver diseases—Meta-analytic assessment. Cancer Med. 2019, 8, 1054–1065. [Google Scholar] [CrossRef]
- Wood, T.E.; Dalili, S.; Simpson, C.D.; Hurren, R.; Mao, X.; Saiz, F.S.; Gronda, M.; Eberhard, Y.; Minden, M.D.; Bilan, P.J.; et al. A novel inhibitor of glucose uptake sensitizes cells to FAS-induced cell death. Mol. Cancer Ther. 2008, 7, 3546–3555. [Google Scholar] [CrossRef]
- Liao, C.-Y.; Lee, C.-C.; Tsai, C.-C.; Hsueh, C.-W.; Wang, C.-C.; Chen, I.-H.; Tsai, M.-K.; Liu, M.-Y.; Hsieh, A.-T.; Su, K.-J.; et al. Novel Investigations of Flavonoids as Chemopreventive Agents for Hepatocellular Carcinoma. BioMed Res. Int. 2015, 2015, 1–26. [Google Scholar] [CrossRef]
- Poulsen, S.B.; Fenton, R.A.; Rieg, T. Sodium-glucose cotransport. Curr. Opin. Nephrol. Hypertens. 2015, 24, 463–469. [Google Scholar] [CrossRef]
- Zhang, X.L.; Zhu, Q.Q.; Chen, Y.H.; Li, X.L.; Chen, F.; Huang, J.A.; Xu, B. Cardiovascular Safety, Long-Term Noncardiovascular Safety, and Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Type 2 Diabetes Mellitus: A Systemic Review and Meta-Analysis with Trial Sequential Analysis. J. Am. Heart Assoc. 2018, 7, e007165. [Google Scholar] [CrossRef]
- Shao, S.; Chang, K.; Chien, R.; Lin, S.; Hung, M.; Chan, Y.; Yang, Y.K.; Lai, E.C. Effects of sodium-glucose co-transporter-2 inhibitors on serum alanine aminotransferase levels in people with type 2 diabetes: A multi-institutional cohort study. Diabetes Obes. Metab. 2019, 22, 128–134. [Google Scholar] [CrossRef]
- Zhou, J.; Zhu, J.; Yu, S.-J.; Ma, H.-L.; Chen, J.; Ding, X.-F.; Chen, G.; Liang, Y.; Zhang, Q. Sodium-glucose co-transporter-2 (SGLT-2) inhibition reduces glucose uptake to induce breast cancer cell growth arrest through AMPK/mTOR pathway. Biomed. Pharmacother. 2020, 132, 110821. [Google Scholar] [CrossRef]
- Hendryx, M.; Dong, Y.; Ndeke, J.M.; Luo, J. Sodium-glucose cotransporter 2 (SGLT2) inhibitor initiation and hepatocellular carcinoma prognosis. PLoS ONE 2022, 17, e0274519. [Google Scholar] [CrossRef]
- Obara, K.; Shirakami, Y.; Maruta, A.; Ideta, T.; Miyazaki, T.; Kochi, T.; Sakai, H.; Tanaka, T.; Seishima, M.; Shimizu, M. Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice. Oncotarget 2017, 8, 58353–58363. [Google Scholar] [CrossRef]
- Crane, R.K.; Sols, A. The non-competitive inhibition of brain hexokinase by glucose-6-phosphate and related compounds. J. Biol. Chem. 1954, 210, 597–606. [Google Scholar] [CrossRef]
- Maher, J.C.; Krishan, A.; Lampidis, T.J. Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-d-glucose in tumor cells treated under hypoxic vs. aerobic conditions. Cancer Chemother. Pharmacol. 2003, 53, 116–122. [Google Scholar] [CrossRef]
- Wang, Z.; Zhang, L.; Zhang, D.; Sun, R.; Wang, Q.; Liu, X. Glycolysis inhibitor 2-deoxy-D-glucose suppresses carcinogen-induced rat hepatocarcinogenesis by restricting cancer cell metabolism. Mol. Med. Rep. 2015, 11, 1917–1924. [Google Scholar] [CrossRef] [PubMed]
- Vijayaraghavan, R.; Kumar, D.; Dube, S.N.; Singh, R.; Pandey, K.S.; Bag, B.C.; Kaushik, M.P.; Sekhar, K.; Dwarakanath, B.S.; Ravindranath, T. Acute toxicity and cardio-respiratory effects of 2-deoxy-D-glucose: A promising radio sensitiser. Biomed. Environ. Sci. 2006, 19, 96–103. [Google Scholar] [PubMed]
- Zhang, Y.; Huang, F.; Wang, J.; Luo, H.; Wang, Z. 2-DG-Regulated RIP and c-FLIP Effect on Liver Cancer Cell Apoptosis Induced by TRAIL. Med. Sci. Monit. 2015, 21, 3442–3448. [Google Scholar] [CrossRef] [PubMed]
- Laszlo, J.; Stengle, J.; Burk, D.; Landau, B.R. Certain Metabolic and Pharmacologic Effects in Cancer Patients Given Infusions of 2-Deoxy-D-Glucose. J. Natl. Cancer Inst. 1958, 21, 485–494. [Google Scholar] [CrossRef]
- Stein, M.; Lin, H.; Jeyamohan, C.; Dvorzhinski, D.; Gounder, M.; Bray, K.; Eddy, S.; Goodin, S.; White, E.; DiPaola, R.S. Targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignancies. Prostate 2010, 70, 1388–1394. [Google Scholar] [CrossRef]
- Singh, D.; Banerji, A.K.; Dwarakanath, B.S.; Tripathi, R.P.; Gupta, J.P.; Mathew, T.L.; Ravindranath, T.; Jain, V. Optimizing cancer radiotherapy with 2-deoxy-d-glucose dose escalation studies in patients with glioblastoma multiforme. Strahlenther. Onkol. 2005, 181, 507–514. [Google Scholar] [CrossRef]
- Dwarakanath, B.; Prasanna, V.K.; Venkataramana, N.K.; Santhosh, V. Differential responses of tumors and normal brain to the combined treatment of 2-DG and radiation in glioablastoma. J. Cancer Res. Ther. 2009, 5, 44–47. [Google Scholar] [CrossRef]
- Kankotia, S.; Stacpoole, P.W. Dichloroacetate and cancer: New home for an orphan drug? Biochim. Biophys. Acta 2014, 1846, 617–629. [Google Scholar] [CrossRef]
- Stockwin, L.H.; Yu, S.X.; Borgel, S.; Hancock, C.; Wolfe, T.L.; Phillips, L.R.; Hollingshead, M.G.; Newton, D.L. Sodium dichloroacetate selectively targets cells with defects in the mitochondrial ETC. Int. J. Cancer 2010, 127, 2510–2519. [Google Scholar] [CrossRef]
- Shen, Y.-C.; Ou, D.-L.; Hsu, C.; Lin, K.-L.; Chang, C.-Y.; Lin, C.-Y.; Liu, S.-H.; Cheng, A.-L. Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma. Br. J. Cancer 2013, 108, 72–81. [Google Scholar] [CrossRef]
- Chu, Q.S.-C.; Sangha, R.; Spratlin, J.; Vos, L.J.; Mackey, J.R.; McEwan, A.J.B.; Venner, P.; Michelakis, E.D. A phase I open-labeled, single-arm, dose-escalation, study of dichloroacetate (DCA) in patients with advanced solid tumors. Investig. New Drugs 2015, 33, 603–610. [Google Scholar] [CrossRef]
- Dai, Y.; Xiong, X.; Huang, G.; Liu, J.; Sheng, S.; Wang, H.; Qin, W. Dichloroacetate Enhances Adriamycin-Induced Hepatoma Cell Toxicity In Vitro and In Vivo by Increasing Reactive Oxygen Species Levels. PLoS ONE 2014, 9, e92962. [Google Scholar] [CrossRef]
- Ganapathy-Kanniappan, S.; Geschwind, J.-F.H.; Kunjithapatham, R.; Buijs, M.; Vossen, J.A.; Tchernyshyov, I.; Cole, R.N.; Syed, L.H.; Rao, P.P.; Ota, S.; et al. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is pyruvylated during 3-bromopyruvate mediated cancer cell death. Anticancer. Res. 2009, 29, 4909–4918. [Google Scholar]
- Ganapathy-Kanniappan, S.; Kunjithapatham, R.; Geschwind, J.-F. Glyceraldehyde-3-Phosphate Dehydrogenase: A Promising Target for Molecular Therapy in Hepatocellular Carcinoma. Oncotarget 2012, 3, 940–953. [Google Scholar] [CrossRef]
- Ko, Y.H.; Pedersen, P.L.; Geschwind, J. Glucose catabolism in the rabbit VX2 tumor model for liver cancer: Characterization and targeting hexokinase. Cancer Lett. 2001, 173, 83–91. [Google Scholar] [CrossRef]
- El Sayed, S.M.; Baghdadi, H.; Zolaly, M.; Al-Maramhy, H.H.; Ayat, M.; Donki, J.G. The promising anticancer drug 3-bromopyruvate is metabolized through glutathione conjugation which affects chemoresistance and clinical practice: An evidence-based view. Med. Hypotheses 2017, 100, 67–77. [Google Scholar] [CrossRef]
- Buijs, M.; Wijlemans, J.W.; Kwak, B.K.; Ota, S.; Geschwind, J.-F.H. Antiglycolytic Therapy Combined with an Image-guided Minimally Invasive Delivery Strategy for the Treatment of Breast Cancer. J. Vasc. Interv. Radiol. 2013, 24, 737–743. [Google Scholar] [CrossRef]
- Vali, M.; Liapi, E.; Kowalski, J.; Hong, K.; Khwaja, A.; Torbenson, M.S.; Georgiades, C.; Geschwind, J.-F.H. Intraarterial Therapy with a New Potent Inhibitor of Tumor Metabolism (3-bromopyruvate): Identification of Therapeutic Dose and Method of Injection in an Animal Model of Liver Cancer. J. Vasc. Interv. Radiol. 2007, 18, 95–101. [Google Scholar] [CrossRef]
- Liapi, E.; Geschwind, J.-F.H.; Vali, M.; Khwaja, A.A.; Prieto-Ventura, V.; Buijs, M.; Vossen, J.A.; Ganapathy, S.; Wahl, R.L. Assessment of Tumoricidal Efficacy and Response to Treatment with 18F-FDG PET/CT After Intraarterial Infusion with the Antiglycolytic Agent 3-Bromopyruvate in the VX2 Model of Liver Tumor. J. Nucl. Med. 2011, 52, 225–230. [Google Scholar] [CrossRef]
- Ota, S.; Geschwind, J.-F.H.; Buijs, M.; Wijlemans, J.W.; Kwak, B.K.; Ganapathy-Kanniappan, S. Ultrasound-guided direct delivery of 3-bromopyruvate blocks tumor progression in an orthotopic mouse model of human pancreatic cancer. Target. Oncol. 2013, 8, 145–151. [Google Scholar] [CrossRef]
- Chapiro, J.; Sur, S.; Savic, L.J.; Ganapathy-Kanniappan, S.; Reyes, J.; Duran, R.; Thiruganasambandam, S.C.; Moats, C.R.; Lin, M.; Luo, W.; et al. Systemic Delivery of Microencapsulated 3-Bromopyruvate for the Therapy of Pancreatic Cancer. Clin. Cancer Res. 2014, 20, 6406–6417. [Google Scholar] [CrossRef] [PubMed]
- Ihrlund, L.S.; Hernlund, E.; Khan, O.; Shoshan, M.C. 3-Bromopyruvate as inhibitor of tumour cell energy metabolism and chemopotentiator of platinum drugs. Mol. Oncol. 2008, 2, 94–101. [Google Scholar] [CrossRef] [PubMed]
- Olesen, K.H.; Sigurd, B.; Steiness, E.; Leth, A. Bumetanide, a new potent diuretic. A clinical evaluation in congestive heart failure. Acta Med. Scand. 1973, 193, 94–101. [Google Scholar]
- Carta, F.; Supuran, C.T. Diuretics with carbonic anhydrase inhibitory action: A patent and literature review (2005–2013). Expert Opin. Ther. Patents 2013, 23, 681–691. [Google Scholar] [CrossRef] [PubMed]
- Supuran, C.T. Diuretics: From Classical Carbonic Anhydrase Inhibitors to Novel Applications of the Sulfonamides. Curr. Pharm. Des. 2008, 14, 641–648. [Google Scholar] [CrossRef]
- Parks, S.K.; Chiche, J.; Pouyssegur, J. pH control mechanisms of tumor survival and growth. J. Cell. Physiol. 2011, 226, 299–308. [Google Scholar] [CrossRef]
- Temperini, C.; Cecchi, A.; Scozzafava, A.; Supuran, C.T. Carbonic anhydrase inhibitors. Sulfonamide diuretics revisited—Old leads for new applications? Org. Biomol. Chem. 2008, 6, 2499–2506. [Google Scholar] [CrossRef]
- Swietach, P. What is pH regulation, and why do cancer cells need it? Cancer Metastasis Rev. 2019, 38, 5–15. [Google Scholar] [CrossRef]
- Lubowitz, H. The effect of bumetanide on cation transport in human red blood cells. J. Pharmacol. Exp. Ther. 1977, 203, 92–96. [Google Scholar]
- Chang, J.M.; Chung, J.W.; Jae, H.J.; Eh, H.; Son, K.R.; Lee, K.C.; Park, J.H. Local Toxicity of Hepatic Arterial Infusion of Hexokinase II Inhibitor, 3-Bromopyruvate: In Vivo Investigation in Normal Rabbit Model. Acad. Radiol. 2007, 14, 85–92. [Google Scholar] [CrossRef]
Category | Name of the Drug | Mechanism of Action | In Vivo or In Vitro Studies, Type of Cancer |
---|---|---|---|
Targeting glucose transporters | GLUT-1 antibody | Inhibits GLUT 1 | Inhibits proliferation and induces apoptosis in NSCL and breast cancer [24]. |
Ritonavir | Inhibits Protease and GLUT 4 | Has shown a cytotoxic effect on multiple myeloma, breast, ovarian, and melanoma cancer cell lines [25]. | |
BAY-876 | GLUT 1 receptor antagonist | Can be effective in HCC [26]. | |
Fasentin | GLUT 1 receptor antagonist | Limited data are available. | |
Phloretin | Blocks GLUT 2 | Induces apoptosis in HCC and suppresses the protein kinase C pathway in melanoma cell lines [27,28]. | |
Silybin | Blocks GLUT 4 | Inhibits growth in HCC cell lines [29]. | |
Quercetin | Blocks GLUT 1 | An increase in the BAX/BCL-2 ratio induces apoptosis in HCC cell lines [30]. | |
Canagliflozin | SGLT2 inhibitor | Reduced growth of liver cancer cells [31]. | |
Targeting enzymes involved in glycolysis | 2-deoxy-D-glucose | Inhibits hexokinase inhibitor | Cellular ATP depletion and apoptosis in HepG2 and Hep3B HCC cell lines [32,33]. Evaluated in prostate cancer, glioma blastoma multiforme, and anaplastic astrocytoma [34,35,36]. |
Dichloroacetate | Inhibits pyruvate dehydrogenase kinase | Redirecting cellular metabolism and reversing the Warburg effect in different tumor cells, including the breast, prostate, medullary thyroid, lung, myeloma, endometrial, and glioblastoma multiforme [37,38,39,40,41,42]. | |
3-Bromopyruvate | Inhibits GAPDH and hexokinase | Effectively suppresses glycolysis and impedes ATP production, leading to apoptosis. Both in vitro and in vivo showed antitumor effects on HCC [43,44]. | |
Bumetanide | Inhibits carbonic anhydrase IX (CAIX) and XII (CAXII) | Lactic acid accumulation and decrease in cellular pH. Studies in an N1S1 HCC tumor model in rats have been shown to sever tumor necrosis [45]. |
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Pourbaghi, M.; Haghani, L.; Zhao, K.; Karimi, A.; Marinelli, B.; Erinjeri, J.P.; Geschwind, J.-F.H.; Yarmohammadi, H. Anti-Glycolytic Drugs in the Treatment of Hepatocellular Carcinoma: Systemic and Locoregional Options. Curr. Oncol. 2023, 30, 6609-6622. https://doi.org/10.3390/curroncol30070485
Pourbaghi M, Haghani L, Zhao K, Karimi A, Marinelli B, Erinjeri JP, Geschwind J-FH, Yarmohammadi H. Anti-Glycolytic Drugs in the Treatment of Hepatocellular Carcinoma: Systemic and Locoregional Options. Current Oncology. 2023; 30(7):6609-6622. https://doi.org/10.3390/curroncol30070485
Chicago/Turabian StylePourbaghi, Miles, Leila Haghani, Ken Zhao, Anita Karimi, Brett Marinelli, Joseph P. Erinjeri, Jean-Francois H. Geschwind, and Hooman Yarmohammadi. 2023. "Anti-Glycolytic Drugs in the Treatment of Hepatocellular Carcinoma: Systemic and Locoregional Options" Current Oncology 30, no. 7: 6609-6622. https://doi.org/10.3390/curroncol30070485
APA StylePourbaghi, M., Haghani, L., Zhao, K., Karimi, A., Marinelli, B., Erinjeri, J. P., Geschwind, J.-F. H., & Yarmohammadi, H. (2023). Anti-Glycolytic Drugs in the Treatment of Hepatocellular Carcinoma: Systemic and Locoregional Options. Current Oncology, 30(7), 6609-6622. https://doi.org/10.3390/curroncol30070485