Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, Schleusenweg 2-16, 60528 Frankfurt, Germany.
BMC Cancer. 2011 Jul 26;11:315. doi: 10.1186/1471-2407-11-315.
Even in the presence of oxygen, malignant cells often highly depend on glycolysis for energy generation, a phenomenon known as the Warburg effect. One strategy targeting this metabolic phenotype is glucose restriction by administration of a high-fat, low-carbohydrate (ketogenic) diet. Under these conditions, ketone bodies are generated serving as an important energy source at least for non-transformed cells.
To investigate whether a ketogenic diet might selectively impair energy metabolism in tumor cells, we characterized in vitro effects of the principle ketone body 3-hydroxybutyrate in rat hippocampal neurons and five glioma cell lines. In vivo, a non-calorie-restricted ketogenic diet was examined in an orthotopic xenograft glioma mouse model.
The ketone body metabolizing enzymes 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and 2), 3-oxoacid-CoA transferase 1 (OXCT1) and acetyl-CoA acetyltransferase 1 (ACAT1) were expressed at the mRNA and protein level in all glioma cell lines. However, no activation of the hypoxia-inducible factor-1α (HIF-1α) pathway was observed in glioma cells, consistent with the absence of substantial 3-hydroxybutyrate metabolism and subsequent accumulation of succinate. Further, 3-hydroxybutyrate rescued hippocampal neurons from glucose withdrawal-induced cell death but did not protect glioma cell lines. In hypoxia, mRNA expression of OXCT1, ACAT1, BDH1 and 2 was downregulated. In vivo, the ketogenic diet led to a robust increase of blood 3-hydroxybutyrate, but did not alter blood glucose levels or improve survival.
In summary, glioma cells are incapable of compensating for glucose restriction by metabolizing ketone bodies in vitro, suggesting a potential disadvantage of tumor cells compared to normal cells under a carbohydrate-restricted ketogenic diet. Further investigations are necessary to identify co-treatment modalities, e.g. glycolysis inhibitors or antiangiogenic agents that efficiently target non-oxidative pathways.
即使在氧气存在的情况下，恶性细胞通常也高度依赖糖酵解来产生能量，这种现象被称为沃伯格效应。一种针对这种代谢表型的策略是通过给予高脂肪、低碳水化合物（生酮）饮食来限制葡萄糖。在这些条件下，酮体被生成，至少对于未转化的细胞来说，酮体是一种重要的能量来源。
为了研究生酮饮食是否可能选择性地损害肿瘤细胞的能量代谢，我们在体外研究了主要酮体 3-羟丁酸在大鼠海马神经元和 5 种神经胶质瘤细胞系中的作用。在体内，我们在原位异种移植神经胶质瘤小鼠模型中检查了非热量限制的生酮饮食。
酮体代谢酶 3-羟丁酸脱氢酶 1 和 2（BDH1 和 2）、3-氧代酸-CoA 转移酶 1（OXCT1）和乙酰辅酶 A 乙酰转移酶 1（ACAT1）在所有神经胶质瘤细胞系中均在 mRNA 和蛋白质水平上表达。然而，在神经胶质瘤细胞中没有观察到缺氧诱导因子-1α（HIF-1α）途径的激活，这与大量 3-羟丁酸代谢和随后琥珀酸的积累一致。此外，3-羟丁酸挽救了葡萄糖剥夺诱导的海马神经元死亡，但不能保护神经胶质瘤细胞系。在缺氧条件下，OXCT1、ACAT1、BDH1 和 2 的 mRNA 表达下调。在体内，生酮饮食导致血液 3-羟丁酸水平大幅增加，但不改变血糖水平或改善存活率。
总之，神经胶质瘤细胞在体外无法通过代谢酮体来补偿葡萄糖限制，这表明在碳水化合物限制的生酮饮食下，与正常细胞相比，肿瘤细胞可能处于潜在劣势。需要进一步研究以确定联合治疗方式，例如糖酵解抑制剂或抗血管生成剂，这些药物可以有效地靶向非氧化途径。
