Pharmacological Double Inhibition of Glycolysis in glioblastoma Multiforme Cells Maximizes Cancer Cell Killing: A Synergism between Citrate and 3-bromopyruvate

Faten M. Omran¹, Hussam Baghdadi², Tamer M. Soliman³, Osama Alhadramy⁴, Momen El-shazley^{5, 6}, Samer A. El-Sawy⁷, Hytham Mahmoud Abdel-Latif¹, Wafaa A. Abdellah¹, Azza Mahmoud Ahmed Abouelella¹, Amr El-Dardear⁸, Mohamed Abdel-haleem⁹, Elhussainy MA Elhussainy¹⁰, Hassan El-Alaf¹¹, Nassar Ayoub¹², Sayed Mostafa El Sayed^{13, 14}, Hesham I. Abdallah^{13, 14}, Salah Mohamed El Sayed^{2, 7,} , Mongi Ayat¹⁵ and Ahmed Mohamed Shehata^{16, 17}

¹Department of Medical Pharmacology, Sohag Faculty of Medicine, Sohag University, Egypt

²Department of Clinical Biochemistry and Molecular Medicine, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

³Department of Clinical Pathology, Sohag Faculty of Medicine, Sohag University, Egypt

⁴Division of Cardiology, Department of Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

⁵Department of Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

⁶Department of Occupational Diseases and Toxigenomics, Sohag Faculty of Medicine, Sohag University, Egypt

⁷Department of Medical Biochemistry, Sohag Faculty of Medicine, Sohag University, Egypt

⁸Department of Pediatrics, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

⁹Department of Ear, Nose and Throat, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

¹⁰Department of Medical Physiology, Kafr Elshekh Faculty of Medicine, Kafr Elsheikh University, Egypt

¹¹Department of Medical Physiology, Sohag Faculty of Medicine, Sohag University, Egypt

¹²Anatomy and Embryology Department, Faculty of Medicine, Sohag University, Egypt

¹³Anatomy and Embryology Department, Faculty of Medicine, Ain Shams University, Egypt

¹⁴4Anatomy and Embryology Department, Faculty of Medicine, Taibah University, Saudi Arabia

¹⁵Division of Hematology, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

¹⁶Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

¹⁷7Department of Pharmacology and toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt

Cite this paper:
Faten M. Omran, Hussam Baghdadi, Tamer M. Soliman, Osama Alhadramy, Momen El-shazley, Samer A. El-Sawy, Hytham Mahmoud Abdel-Latif, Wafaa A. Abdellah, Azza Mahmoud Ahmed Abouelella, Amr El-Dardear, Mohamed Abdel-haleem, Elhussainy MA Elhussainy, Hassan El-Alaf, Nassar Ayoub, Sayed Mostafa El Sayed, Hesham I. Abdallah, Salah Mohamed El Sayed, Mongi Ayat and Ahmed Mohamed Shehata. Pharmacological Double Inhibition of Glycolysis in glioblastoma Multiforme Cells Maximizes Cancer Cell Killing: A Synergism between Citrate and 3-bromopyruvate. American Journal of Pharmacological Sciences. 2020; 8(1):1-6. doi: 10.12691/ajps-8-1-1

Abstract

Glioblastoma multiform (GBM) tumors are the most aggressive and diffusely infiltrating brain tumors in human patients. Despite surgery, modern chemotherapy and anti-angiogenesis treatments, GBM tumors regrow rapidly and end patients’ lives in a relatively short time. GBM tumors aggressively invade and infiltrate adjacent normal brain tissues. GBM cells are driven by glycolysis (glucose oxidation to produce ATP and lactate in cancer cells). In this study, we cultured rat C6 GBM cells and human GBM cells (U373MG) to be treated using glycolysis inhibitors. Citrate is a natural product enormously available in citrus fruits and has many pharmacological uses e.g. to treat urate renal stones. Citric acid was recently reported to exert cardioprotective effects on myocardial ischemia/reperfusion injury. Serial doses of citrate (glycolytic inhibitor of phosphofructokinase) were lethal to human GBM cell lines at relatively high doses (in millimolar range). Using the combination drug index, low effective doses of citrate (1, 3 and 5 mM) exerted a synergistic anticancer effect with low effective doses of 3-bromopyruvate (15 and 25 µM). Combination index was < 1 and denoted strong synergism between citrate and 3-bromopyruvate. As 3-bromopyruvate is another glycolysis inhibitor (hexokinase II inhibitor) in addition to citrate itself, double inhibition of glycolysis was evident when combining both citrate and 3-bromopyruvate. Both drugs benefited from tumor biology as citrate is acidic in solution and does better in acidic tumor microenvironment and same thing applies to 3-bromopyruvate that is also acidic in solution. In addition, 3-bromopyruvate is a structural analog and competitive antagonist of lactate (The Warburg effect) to deprive cancer cells of vital benefits of lactate. Lactate-based benefits to cancer cells include enhancing angiogenesis, metastasis, invasion, proliferation, migration, chemoresistance, radioresistance and acidic tumor microenvironment. Our data confirmed that pharmacological glycolysis double inhibition significantly, maximally and synergistically distorted GBM cells morphology and reduced cellular viability. This may carry a lot of hope for treating the dismal outcome in those patients.

Keywords:
Glycolysis double inhibition hexokinase pharmacological antagonist phosphofructokinase glioblastoma viability

This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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