Seyfried Thomas N, Kiebish Michael A, Marsh Jeremy, Shelton Laura M, Huysentruyt Leanne C, Mukherjee Purna
Biology Department, Boston College, Chestnut Hill, MA 02467, USA.
Biochim Biophys Acta. 2011 Jun;1807(6):577-94. doi: 10.1016/j.bbabio.2010.08.009. Epub 2010 Sep 8.
Malignant brain tumors are a significant health problem in children and adults. Conventional therapeutic approaches have been largely unsuccessful in providing long-term management. As primarily a metabolic disease, malignant brain cancer can be managed through changes in metabolic environment. In contrast to normal neurons and glia, which readily transition to ketone bodies (β-hydroxybutyrate) for energy under reduced glucose, malignant brain tumors are strongly dependent on glycolysis for energy. The transition from glucose to ketone bodies as a major energy source is an evolutionary conserved adaptation to food deprivation that permits the survival of normal cells during extreme shifts in nutritional environment. Only those cells with a flexible genome and normal mitochondria can effectively transition from one energy state to another. Mutations restrict genomic and metabolic flexibility thus making tumor cells more vulnerable to energy stress than normal cells. We propose an alternative approach to brain cancer management that exploits the metabolic flexibility of normal cells at the expense of the genetically defective and metabolically challenged tumor cells. This approach to brain cancer management is supported from recent studies in mice and humans treated with calorie restriction and the ketogenic diet. Issues of implementation and use protocols are presented for the metabolic management of brain cancer.
恶性脑肿瘤是儿童和成人面临的一个重大健康问题。传统治疗方法在提供长期治疗方面大多未取得成功。作为一种主要的代谢性疾病，恶性脑癌可通过改变代谢环境来进行治疗。与正常神经元和神经胶质细胞不同，在葡萄糖减少的情况下，正常神经元和神经胶质细胞会很容易地转变为利用酮体（β-羟基丁酸）来获取能量，而恶性脑肿瘤则强烈依赖糖酵解来获取能量。从葡萄糖到酮体作为主要能量来源的转变是一种进化上保守的对食物匮乏的适应，它使正常细胞在营养环境发生极端变化时能够存活下来。只有那些具有灵活基因组和正常线粒体的细胞才能有效地从一种能量状态转变为另一种能量状态。突变会限制基因组和代谢的灵活性，从而使肿瘤细胞比正常细胞更容易受到能量应激的影响。我们提出了一种治疗脑癌的替代方法，该方法利用正常细胞的代谢灵活性，以牺牲基因缺陷和代谢有问题的肿瘤细胞为代价。最近对接受卡路里限制和生酮饮食治疗的小鼠和人类的研究支持了这种脑癌治疗方法。本文还介绍了脑癌代谢管理的实施问题和使用方案。
