title: The promising anticancer drug 3-bromopyruvate is metabolized through glutathione conjugation which affects chemoresistance and clinical practice: An evidence-based view.
abstract: 3-Bromopyruvate (3BP) is a promising effective anticancer drug against many different tumors in children and adults. 3BP exhibited strong anticancer effects in both preclinical and human studies e.g. energy depletion, oxidative stress, anti-angiogenesis, anti-metastatic effects, targeting cancer stem cells and antagonizing the Warburg effect. There is no report about 3BP metabolism to guide researchers and oncologists to improve clinical practice and prevent drug resistance. In this article, we provide evidences that 3BP is metabolized through glutathione (GSH) conjugation as a novel report where 3BP was confirmed to be attached to GSH followed by permanent loss of pharmacological effects in a picture similar to cisplatin. Both cisplatin and 3BP are alkylating agents. Reported decrease in endogenous cellular GSH content upon 3BP treatment was confirmed to be due to the formation of 3BP-GSH complex i.e. GSH consumption for conjugation with 3BP. Cancer cells having high endogenous GSH exhibit resistance to 3BP while 3BP sensitive cells acquire resistance upon adding exogenous GSH. Being a thiol blocker, 3BP may attack thiol groups in tissues and serum proteins e.g. albumin and GSH. That may decrease 3BP-induced anticancer effects and the functions of those proteins. We proved here that 3BP metabolism is different from metabolism of hydroxypyruvate that results from metabolism of D-serine using D-amino acid oxidase. Clinically, 3BP administration should be monitored during albumin infusion and protein therapy where GSH should be added to emergency medications. GSH exerts many physiological effects and is safe for human administration both orally and intravenously. Based on that, reported GSH-induced inhibition of 3BP effects makes 3BP effects reversible, easily monitored and easily controlled. This confers a superiority of 3BP over many anticancer agents.
authors.affiliation: Department of Clinical Biochemistry and Molecular Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia; Department of Medical Biochemistry, Sohag Faculty of Medicine, Sohag University, Egypt. Electronic address: salahfazara@yahoo.com.
authors.forename: Salah Mohamed
authors.initials: SM
authors.lastname: El Sayed
authors.affiliation: Department of Clinical Biochemistry and Molecular Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia.
authors.forename: Hussam
authors.initials: H
authors.lastname: Baghdadi
authors.affiliation: Department of Pediatrics, College of Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Zolaly
authors.affiliation: Department of Surgery, College of Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia.
authors.forename: Hamdi H
authors.initials: HH
authors.lastname: Almaramhy
authors.affiliation: Department of Clinical Biochemistry and Molecular Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia.
authors.forename: Mongi
authors.initials: M
authors.lastname: Ayat
authors.affiliation: Integrative Oncology Center, Medical Director, Bangalore 560010, India.
authors.forename: Jagadish G
authors.initials: JG
authors.lastname: Donki
mesh_terms: D000082:Acetaminophen / Q000627:therapeutic use; D000284:Administration, Oral; D000418:Albumins / Q000378:metabolism; D000477:Alkylating Agents / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D019317:Evidence-Based Medicine; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D007262:Infusions, Intravenous; D008545:Melanoma / Q000188:drug therapy; D008962:Models, Theoretical; D011773:Pyruvates / Q000378:metabolism / Q000627:therapeutic use*; D012694:Serine / Q000378:metabolism
chemical_list: D000418:Albumins; D000477:Alkylating Agents; D000970:Antineoplastic Agents; D011773:Pyruvates; D000082:Acetaminophen; D012694:Serine; C017092:bromopyruvate; D005978:Glutathione; D002945:Cisplatin
keywords: 3-Bromopyruvate; Cancer; Conjugation; Glutathione; Metabolism; Paracetamol