El Sayed Salah Mohamed, Baghdadi Hussam, Zolaly Mohammed, Almaramhy Hamdi H, Ayat Mongi, Donki Jagadish G
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.
Department of Clinical Biochemistry and Molecular Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia.
Med Hypotheses. 2017 Mar;100:67-77. doi: 10.1016/j.mehy.2017.01.014. Epub 2017 Jan 23.
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.
3-溴丙酮酸（3BP）是一种有望有效对抗儿童和成人多种不同肿瘤的抗癌药物。3BP在临床前研究和人体研究中均表现出强大的抗癌作用，例如能量消耗、氧化应激、抗血管生成、抗转移作用、靶向癌症干细胞以及拮抗瓦伯格效应。目前尚无关于3BP代谢的报道来指导研究人员和肿瘤学家改善临床实践并预防耐药性。在本文中，我们提供证据表明3BP通过谷胱甘肽（GSH）结合进行代谢，这是一项新的报道，其中证实3BP与GSH结合，随后药理作用永久丧失，情况类似于顺铂。顺铂和3BP都是烷化剂。据报道，3BP处理后细胞内源性GSH含量的降低被证实是由于3BP-GSH复合物的形成，即GSH用于与3BP结合而被消耗。内源性GSH含量高的癌细胞对3BP具有抗性，而3BP敏感细胞在添加外源性GSH后会获得抗性。作为一种硫醇阻断剂，3BP可能会攻击组织和血清蛋白（如白蛋白和GSH）中的硫醇基团。这可能会降低3BP诱导的抗癌作用以及这些蛋白质的功能。我们在此证明3BP的代谢不同于由D-丝氨酸通过D-氨基酸氧化酶代谢产生的羟基丙酮酸的代谢。临床上，在白蛋白输注和蛋白质治疗期间应监测3BP的给药情况，应急药物中应添加GSH。GSH具有多种生理作用，口服和静脉注射对人体给药都是安全的。基于此，报道的GSH诱导的对3BP作用的抑制使得3BP的作用具有可逆性、易于监测和易于控制。这赋予了3BP相对于许多抗癌药物的优势。
