Effects of three modifiers of glycolysis on ATP, lactate, hypoxia, and growth in human tumor cell lines in vivo
Effects of three modifiers of glycolysis on ATP, lactate, hypoxia, and growth in human tumor cell lines in vivo
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DOI：
10.1007/s00066-011-0054-3
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发表时间：
2012-02
影响因子：
3.1
通讯作者：
A. Yaromina;S. Meyer;C. Fabian;K. Zaleska;U. Sattler;L. Kunz-Schughart;W. Mueller‐Klieser;D. Zips;M. Baumann
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文献类型：
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作者：
A. Yaromina;S. Meyer;C. Fabian;K. Zaleska;U. Sattler;L. Kunz-Schughart;W. Mueller‐Klieser;D. Zips;M. Baumann
临床数据表明，高治疗前乳酸含量与各种类型癌症患者的预后不良、晚期、进行性和转移性疾病密切相关[2，33，34]。在最近的一项实验研究中，发现与缺氧无关的高预处理乳酸含量也与一组人鳞状细胞癌（hSCC）异种移植物中临床相关分次照射后较低的肿瘤控制率显著相关[20，22]。乳酸盐在肿瘤中广泛产生和积累，主要是由于糖酵解通量增加，这是由葡萄糖和单羧酸盐的膜基转运蛋白以及糖酵解酶的表达上调和生化激活引起的，这是代谢和致癌调节的结果[23]。照射后高乳酸水平与较低肿瘤控制概率的相关性表明，乳酸可能直接导致辐射抗性，也可能是反映辐射抗性的糖酵解途径中高周转率的生物标志物。因此，抑制糖酵解以降低抗氧化代谢物（如乳酸盐）的水平可能会改善治疗反应。有许多关于肿瘤细胞代谢从糖酵解转变为葡萄糖氧化的研究，例如通过上调丙酮酸脱氢酶活性或抑制乳酸脱氢酶活性[21]。生物化学抑制剂或酶表达水平的遗传敲低预期刺激丙酮酸氧化并减少乳酸产生。然而，大多数研究在体外测试了生化抑制剂的疗效，而细胞外葡萄糖浓度、细胞葡萄糖摄取、乳酸释放和蓄积之间的复杂关系（部分由肿瘤微环境（例如缺氧、灌注）决定）可能影响体内代谢微环境[22，37]。在本研究中，我们测试了参与代谢反应级联的重要调节剂的几种生化抑制剂[9，25]是否可以改变ATP和乳酸水平并改变肿瘤生长，而不会显著增强已知的放射抗性因素，如缺氧[28，30，32]。为此，在两个头颈部hSCC和移植到免疫缺陷裸鼠中的人结直肠腺癌细胞系中评价了丙酮酸脱氢酶激酶（PDK）二氯乙酸盐（DCA）[19]、乳酸脱氢酶（LDH）草氨酸钠（OXA）[18]和单羧酸转运蛋白（MCT）α-氰基-4-羟基肉桂酸盐（CHC）[15]的抑制剂。
Clinical data demonstrate that high pretreatment lactate content is strongly associated with poor prognosis, advanced, progressive, and metastatic disease in patients with various types of cancer [2, 33, 34]. In a recent experimental study, it was found that high pretreatment lactate content independent of hypoxia also significantly correlates with lower tumor control rates after clinically relevant fractionated irradiation in a panel of human squamous cell carcinoma (hSCC) xenografts [20, 22]. Lactate is extensively produced and accumulated in the tumors mainly due to increased glycolytic flux, which is caused by upregulated expression and biochemical activation of membrane-based transporters for glucose and monocarboxylates and of glycolytic enzymes as a consequence of metabolic and oncogenic regulation [23]. The association of high lactate levels with lower tumor control probability after irradiation suggests that lactate may either directly contribute to radioresistance or may be a biomarker of a high turnover rate in the glycolytic pathway reflecting radioresistance. Inhibition of glycolysis to reduce the levels of antioxidant metabolites such as lactate may, therefore, lead to improved treatment response. There are a number of studies on shifting tumor cell metabolism from glycolysis to glucose oxidation, eg, by upregulation of pyruvate dehydrogenase activity or by inhibition of lactate dehydrogenase activity [21]. Biochemical inhibitors or genetic knockdown of enzyme expression levels are expected to stimulate pyruvate oxidation and reduce lactate production. However, most of the studies tested the efficacy of the biochemical inhibitors in vitro, whereas complex relationships between extracellular glucose concentration, cellular glucose uptake, lactate release and accumulation, which are in part determined by tumor microenvironment (eg, hypoxia, perfusion), may influence metabolic micromilieu in vivo [22, 37]. In the present study, we tested whether several biochemical inhibitors of important regulators involved in the cascade of the metabolic reactions [9, 25] can modify ATP and lactate levels and change tumor growth without significant enhancement of known factors of radioresistance such as hypoxia [28, 30, 32]. For this, inhibitors of pyruvate dehydrogenase kinase (PDK) dichloroacetate (DCA)[19], of lactate dehydrogenase (LDH) sodium oxamate (OXA)[18], and of monocarboxylic acid transporters (MCT) α-cyano-4-hydroxycinnamate (CHC)[15] were evaluated in two hSCC of head and neck and in a human colorectal adenocarcinoma cell line transplanted into immunodeficient nude mice.