American Journal of Cancer Prevention
ISSN (Print): 2328-7314 ISSN (Online): 2328-7322 Website: http://www.sciepub.com/journal/ajcp Editor-in-chief: Nabil Abdel-Hamid
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American Journal of Cancer Prevention. 2019, 7(1), 10-14
DOI: 10.12691/ajcp-7-1-2
Open AccessArticle

Glioma Spheroid Cells (3D Tumor Models) Are Less Responsive to 3-Bromopyruvate than Cultured Cells: Lack of Tumors Eradication

Salah Mohamed El Sayed1, 2, , Hussam Baghdadi1, Faten M. Omran3, Ahmed M. Okashah4, Samer A. El-Sawy2, Hytham Mahmoud1, Wafaa A. Abdellah3, Azza Mahmoud Ahmed Abouelela3, Hassan El-Alaf5, Elussainy MA Elussainy6, Sayed Mostafa El Sayed7, 8, Hesham I. Abdallah7, 8, Osama Al-hadramy9, Tamer M. Soliman10, Amr El-Dardear11, Mohamed Abdel-haleem12 and Manal M.H. Nabo13

1Department of Clinical Biochemistry and Molecular Medicine, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

2Department of Medical Biochemistry, Sohag Faculty of Medicine, Sohag University, Egypt

3Department of Medical Pharmacology, Sohag Faculty of Medicine, Sohag University, Egypt

4Academic Affairs Director And Consultant Clinical Immunologist, Al-Madinah Directorate of Health, Al-Madinah Al-Munawwarah, Ministry of Health, Saudi Arabia

5Department of Medical Physiology, Sohag Faculty of Medicine, Sohag University, Egypt

6Department of Medical Physiology, Kafr Elshekh Faculty of Medicine, Kafr Elshekh University, Egypt

7Anatomy and Embryology Department, Faculty of Medicine, Ain Shams University, Egypt

8Anatomy and Embryology Department, Faculty of Medicine, Taibah University, Saudi Arabia

9Division of Cardiology, Department of Medicine, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

100Department of Clinical Pathology, Sohag Faculty of Medicine, Sohag University, Egypt

111Department of Pediatrics, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

122Department of Ear, Nose and Throat, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

133Department of Pediatrics, Al-Rayyan Medical Colleges, Al-Madinah Al-Munawwarah, Saudi Arabia

Pub. Date: October 10, 2019

Cite this paper:
Salah Mohamed El Sayed, Hussam Baghdadi, Faten M. Omran, Ahmed M. Okashah, Samer A. El-Sawy, Hytham Mahmoud, Wafaa A. Abdellah, Azza Mahmoud Ahmed Abouelela, Hassan El-Alaf, Elussainy MA Elussainy, Sayed Mostafa El Sayed, Hesham I. Abdallah, Osama Al-hadramy, Tamer M. Soliman, Amr El-Dardear, Mohamed Abdel-haleem and Manal M.H. Nabo. Glioma Spheroid Cells (3D Tumor Models) Are Less Responsive to 3-Bromopyruvate than Cultured Cells: Lack of Tumors Eradication. American Journal of Cancer Prevention. 2019; 7(1):10-14. doi: 10.12691/ajcp-7-1-2

Abstract

Gliomas and glioblastomas are space-occupying brain tumors with variable aggressive behaviour. Glioblastomas are the most lethal brain tumors and are not responsive to current chemotherapy and radiotherapy. To date, no satisfactory curative treatment exists. 3-bromopyruvate (3BP) is a promising chemotherapeutic that proved effective in treating gliomas and other malignancies in so many reported studies. 3BP is both an alkylating agent and antimetabolite (pharmacological antagonist of lactate, the Warburg effect). Our previous publications proved effectiveness of 3BP in treating glioma cell lines (2D models) and early glioma spheroids (3D models) where 3BP was added early after culturing glioma cells. No report is there regarding treating well-established glioma spheroids (well-established avascular 3D tumor models) using 3BP that we report here. In this study, our data revealed that 3BP effectively and maximally killed cultured glioma cells causing cellular fragmentation that correlated with maximal glioma cell death. However, the picture was less promising when treating well-established 3D glioma spheroids with 3BP where glioma viability and size decreased significantly (in a dose-dependent manner) but not maximally. There was no significant difference in spheroids cell killing at high versus very high doses of 3BP. 3BP may face many problems regarding delivery and targeting to glioma cells inside spheroid body. A similar effect may be faced when treating clinical tumors with 3BP. 3BP formulations inside lipid nanocarriers (liposomes), PEGylated liposomes or targeted liposomes may improve 3BP-induced tumor cells killing. More future research is needed to explore the reasons why 3BP effects in cell lines were not effectively translated into 3D models and how to overcome the obstacles.

Keywords:
3-bromopyruvate spheroids glioma viability

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References:

[1]  Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS et al. Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem Biophys Res Commun. 2004; 324: 269-275.
 
[2]  El Sayed SM, Mahmoud AA, El Sawy SA, Abdelaal EA, Fouad AM, Yousif RS et al. Warburg effect increases steady-state ROS condition in cancer cells through decreasing their antioxidant capacities (anticancer effects of 3-bromopyruvate through antagonizing Warburg effect). Med Hypotheses. 2013; 81: 866-70.
 
[3]  El Sayed SM. Enhancing anticancer effects, decreasing risks and solving practical problems facing 3-bromopyruvate in clinical oncology: 10 years of research experience. Int J Nanomedicine. 2018; 13: 4699-4709.
 
[4]  El Sayed SM, El-Magd RM, Shishido Y, Yorita K, Chung SP, Tran DH, et al. D-Amino acid oxidase-induced oxidative stress, 3-bromopyruvate and citrate inhibit angiogenesis, exhibiting potent anticancer effects. J Bioenerg Biomembr. 2012; 44: 513-23.
 
[5]  El Sayed SM, Abou El-Magd RM, Shishido Y, Chung SP, Sakai T, Watanabe H, et al. D-amino acid oxidase gene therapy sensitizes glioma cells to the antiglycolytic effect of 3-bromopyruvate. Cancer Gene Ther. 2012; 19: 1-18.
 
[6]  El Sayed SM, El-Magd RM, Shishido Y, Chung SP, Diem TH, Sakai T et al. 3-Bromopyruvate antagonizes effects of lactate and pyruvate, synergizes with citrate and exerts novel anti-glioma effects. J Bioenerg Biomembr. 2012; 44: 61-79.
 
[7]  El Sayed SM, Mohamed WG, Seddik MH, Ahmed AA, Mahmoud AG, Amer WH, et al. Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study. Chin J Cancer. 2014; 33: 356-364.
 
[8]  El Sayed SM, Baghdadi H, Zolaly M, Almaramhy HH, Ayat M, Donki JG. 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.
 
[9]  Okano T, Saegusa J, Nishimura K, Takahashi S, Sendo S, Ueda Y, et al. 3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation. Sci Rep. 2017; 7: 42412.
 
[10]  Friedrich J, Seidel C, Ebner R, Kunz-Schughart LA. Spheroid-based drug screen: considerations and practical approach. Nat Protoc. 2009; 4:309-324.