3-bromopyruvate (3BP) is a promising anticancer drug that killed glioblastoma cells using different biochemical and pharmacological mechanisms e.g. inhibiting the glycolytic enzyme hexokinase II and inducing oxidative stress e.g. hydrogen peroxide generation. Glycolysis inhibition inactivates ABC transporters in cancer cells to restore the drug sensitivity in malignant cells. Moreover, the author and Japanese co-researchers proved that 3BP acts as an antimetabolite via antagonizing lactate (Warburg effect) and pyruvate and synergizing the anticancer effects of citrate. Interestingly, the author and Japanese co-researchers were the first to report that 3BP exerted potent anti-angiogenic effects. In this study, 3BP is structurally related to many different compounds that may affect its anticancer effects as pyruvate, lactate, acetic acid, L-alanine and beta-alanine. Author’s experimental data revealed that administering L-alanine alone caused a significant dose-dependent decrease (p<0.001) in C6 glioblastoma cells’ survival. This can be explained in light of the antioxidant merits exerted by the amino acid L-alanine. Unexpectedly, the structural analogs acetic acid, L-alanine and beta-alanine did not protect against 3BP-induced C6 glioma cell death. Treatment of C6 glioblastoma cells with hydrogen peroxide caused a significant glioblastoma cell death (p<0.001) that was significantly antagonized using the natural antioxidants e.g. pyruvate, reduced glutathione and N-acetyl L-cysteine (NAC) (p< 0.001). Lactate did not prevent or antagonize hydrogen peroxide-induced C6 glioma cell death. A combination of small doses of 3BP and citrate was synergistic in suppressing C6 spheroids viability. Moreover, 3BP induced C6 glioma protein depletion in a dose-dependent and time-dependent manner. Protein depletion was evident using SDS-PAGE and is thought to deprive the cancer cells from the necessary protein machineries for synthetic purposes. However, 3BP-induced protein depletion effects should be further studied on normal cells to prevent possible 3BP-induced side effects. Further studies are needed in this respect.
| [1] | El Sayed S, Abou El-Magd R, Shishido Y, Chung S, Diem T, Sakai T, Watanabe H, Kagami S and Fukui K. 3-Bromopyruvate antagonizes effects of lactate and pyruvate, synergizes with citrate and exerts novel anti-glioma effects. Journal of bioenergetics and biomembranes 2012; 44: 61-79.View Article PubMed |
| [2] | El Sayed S, El-Magd A, Shishido Y, Chung S, Sakai T, Watanabe H, Kagami S and Fukui K. D-amino acid oxidase gene therapy sensitizes glioma cells to the antiglycolytic effect of 3-bromopyruvate. Cancer gene therapy 2012; 19: 1-18.View Article PubMed |
| [3] | El Sayed S, Abou El-Magd R, Shishido Y, Yorita K, Chung S, Tran D, Sakai T, Watanabe H, Kagami S and Fukui K. D-Amino acid oxidase-induced oxidative stress, 3-bromopyruvate and citrate inhibit angiogenesis, exhibiting potent anticancer effects. Journal of bioenergetics and biomembranes 2012; 44: 513-523.View Article PubMed |
| [4] | El Sayed SM, Mahmoud AA, El Sawy SA, Abdelaal EA, Fouad AM, Yousif RS, Hashim MS, Hemdan SB, Kadry ZM and Abdelmoaty MA. Warburg effect increases steady-state ROS condition in cancer cells through decreasing their antioxidant capacities (anticancer effects of 3-bromopyruvate through antagonizing Warburg effect). Medical hypotheses 2013; 81: 866-870.View Article PubMed |
| [5] | El Sayed SM. Biochemical Origin of the Warburg Effect in Light of 15 Years of Research Experience: A Novel Evidence-Based View (An Expert Opinion Article). OncoTargets and Therapy 2023; 143-155.View Article PubMed |
| [6] | ZORZANO A, FANDOS C and PALACÍN M. Role of plasma membrane transporters in muscle metabolism. Biochemical Journal 2000; 349: 667-688.View Article PubMed |
| [7] | Warburg O. On the origin of cancer cells. Science 1956; 123: 309-314.View Article PubMed |
| [8] | Mac M and Nałęcz KA. Expression of monocarboxylic acid transporters (MCT) in brain cells: Implication for branched chain α-ketoacids transport in neurons. Neurochemistry international 2003; 43: 305-309.View Article PubMed |
| [9] | Grobben B, De Deyn P and Slegers H. Rat C6 glioma as experimental model system for the study of glioblastoma growth and invasion. Cell and tissue research 2002; 310: 257-270.View Article PubMed |
| [10] | Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwarz S, Rothe G and Hoves S. Inhibitory effect of tumor cell–derived lactic acid on human T cells. Blood 2007; 109: 3812-3819.View Article PubMed |
| [11] | Brizel DM, Schroeder T, Scher RL, Walenta S, Clough RW, Dewhirst MW and Mueller-Klieser W. Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. International Journal of Radiation Oncology* Biology* Physics 2001; 51: 349-353.View Article PubMed |
| [12] | Yabu M, Shime H, Hara H, Saito T, Matsumoto M, Seya T, Akazawa T and Inoue N. IL-23-dependent and-independent enhancement pathways of IL-17A production by lactic acid. International immunology 2011; 23: 29-41.View Article PubMed |
| [13] | Walenta S, Schroeder T and Mueller-Klieser W. Lactate in solid malignant tumors: potential basis of a metabolic classification in clinical oncology. Current medicinal chemistry 2004; 11: 2195-2204.View Article PubMed |
| [14] | Fantin VR, St-Pierre J and Leder P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer cell 2006; 9: 425-434.View Article PubMed |
| [15] | Marín-Hernández A, Rodríguez-Enríquez S, Vital-González PA, Flores-Rodríguez FL, Macías-Silva M, Sosa-Garrocho M and Moreno-Sánchez R. Determining and understanding the control of glycolysis in fast-growth tumor cells: Flux control by an over-expressed but strongly product-inhibited hexokinase. The FEBS journal 2006; 273: 1975-1988.View Article PubMed |
| [16] | Yousefi S, Owens J and Cesario T. Citrate shows specific, dose-dependent lympholytic activity in neoplastic cell lines. Leukemia & lymphoma 2004; 45: 1657-1665.View Article PubMed |
| [17] | Friedrich J, Seidel C, Ebner R and Kunz-Schughart LA. Spheroid-based drug screen: considerations and practical approach. Nature protocols 2009; 4: 309-324.View Article PubMed |
| [18] | Nakano A, Tsuji D, Miki H, Cui Q, Sayed SME, Ikegame A, Oda A, Amou H, Nakamura S and Harada T. Glycolysis inhibition inactivates ABC transporters to restore drug sensitivity in malignant cells. PloS one 2011; 6: e27222.View Article PubMed |
| [19] | El Sayed SM, Baghdadi H, Ahmed NS, Almaramhy HH, Mahmoud AA-A, El-Sawy SA, Ayat M, Elshazley M, Abdel-Aziz W and Abdel-Latif HM. Dichloroacetate is an antimetabolite that antagonizes acetate and deprives cancer cells from its benefits: A novel evidence-based medical hypothesis. Medical Hypotheses 2019; 122: 206-209.View Article PubMed |
| [20] | El Sayed SM, Abdelkreem E, Aboonq MS, Al Thagfan SS, Alahmadi YM, Alhadramy O, Baghdadi H, Hassan M, Omran FM and Mahmoud H. Dichloroacetate is a Novel Safe Treatment for Beta-ketothiolase Deficiency: Towards Better Therapeutic Outcomes (An Original Article). International Journal 2020; 8: 4-8. |
| [21] | El Sayed SM, Mohamed WG, Seddik M-AH, Ahmed A-SA, Mahmoud AG, Amer WH, Nabo MMH, Hamed AR, Ahmed NS and Abd-Allah AA-R. Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study. Chinese journal of cancer 2014; 33: 356.View Article PubMed |
| [22] | El Sayed SM, Baghdadi H, Zolaly M, Almaramhy HH, Ayat M and Donki JG. The promising anticancer drug 3-bromopyruvate is metabolized through glutathione conjugation which affects chemoresistance and clinical practice: An evidence-based view. Medical hypotheses 2017; 100: 67-77.View Article PubMed |
| [23] | El Sayed SM. Enhancing anticancer effects, decreasing risks and solving practical problems facing 3-bromopyruvate in clinical oncology: 10 years of research experience. International journal of nanomedicine 2018; 13: 4699.View Article PubMed |
| [24] | El Sayed SM. Oxidative Stress in Hepatocarcinogenesis and Role of Antioxidant Therapy. In: editors. Handbook of Oxidative Stress in Cancer: Mechanistic Aspects. Springer; 2022. p. 821-838.View Article |
| [25] | Ganapathy-Kanniappan S, Geschwind J-FH, Kunjithapatham R, Buijs M, Vossen JA, Tchernyshyov I, Cole RN, Syed LH, Rao PP and Ota S. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is pyruvylated during 3-bromopyruvate mediated cancer cell death. Anticancer research 2009; 29: 4909-4918. |
