文章：

破坏质子动力学和能量代谢的癌症治疗

Disrupting proton dynamics and energy metabolism for cancer therapy

原文发布日期：2013-08-23

DOI: 10.1038/nrc3579

类型: Review Article

开放获取: 否

要点：

1. In rapidly growing cancer cells, oncogenes and hypoxia stimulate glycolytic metabolism, which generates increased amounts of lactic and carbonic acids.
2. Several pH-regulating systems — Na⁺/H⁺ exchangers (NHEs), carbonic anhydrases (CAIX and CAXII), HCO₃⁻ transporters, lactate/H⁺ symporters (monocarboxylate transporter 1 (MCT1) and MCT4) and intracellular H⁺ pumps — are essential to maintain a permissive intracellular pH (pH_i) to optimize bioenergetic metabolism, cell cycle progression, growth and survival.
3. Cells lacking pH-regulating capabilities can enter growth arrest or can be 'killed' by H⁺. Targeting pH-regulating proteins in isolation (NHE1, CAs, MCTs and H⁺ pumps) impairs tumour progression.
4. Targeting the export of lactic acid from tumour cells (by disrupting MCTs) reduces glycolysis and growth rates, thus sensitizing tumour cells to treatment with mitochondrial complex I inhibitors (such as metformin and phenformin).
5. We propose the development of an acute 'metabolic knife' treatment that combines targeting of pH control and ATP-driven metabolism to eradicate rapidly growing glycolytic tumours.

要点翻译：

1. 在快速生长的癌细胞中，致癌基因与缺氧状态共同刺激糖酵解代谢，导致乳酸和碳酸生成量增加。
2. 多种pH调节系统——包括Na+/H+交换体（NHEs）、碳酸酐酶（CAIX与CAXII）、HCO3−转运蛋白、乳酸/H+同向转运体（单羧酸转运蛋白1（MCT1）与MCT4）以及细胞内H+泵——对维持适宜的细胞内pH值（pHi）至关重要，从而优化生物能代谢、细胞周期进程、生长与存活。
3. 缺乏pH调节能力的细胞可能进入生长停滞状态或被H+“扼杀”。单独靶向pH调节蛋白（NHE1、CAs、MCTs和H+泵）可抑制肿瘤进展。
4. 通过干扰MCTs来靶向肿瘤细胞乳酸外排，能降低糖酵解速率和生长速度，从而增强肿瘤细胞对线粒体复合物I抑制剂（如二甲双胍和苯乙双胍）治疗的敏感性。
5. 我们建议开发一种结合靶向pH调控与ATP驱动代谢的急性“代谢刀”疗法，以根除快速生长的糖酵解依赖性肿瘤。

英文摘要：

Intense interest in the 'Warburg effect' has been revived by the discovery that hypoxia-inducible factor 1 (HIF1) reprogrammes pyruvate oxidation to lactic acid conversion; lactic acid is the end product of fermentative glycolysis. The most aggressive and invasive cancers, which are often hypoxic, rely on exacerbated glycolysis to meet the increased demand for ATP and biosynthetic precursors and also rely on robust pH-regulating systems to combat the excessive generation of lactic and carbonic acids. In this Review, we present the key pH-regulating systems and synthesize recent advances in strategies that combine the disruption of pH control with bioenergetic mechanisms. We discuss the possibility of exploiting, in rapidly growing tumours, acute cell death by 'metabolic catastrophe'.

摘要翻译： 

对“瓦氏效应”的浓厚兴趣已被缺氧诱导因子1（HIF1）重编程丙酮酸氧化为乳酸转化的发现所重新唤起；乳酸是发酵糖酵解的最终产物。最具侵袭性和浸润性的癌症，常常是缺氧的，依赖加剧的糖酵解来满足对ATP和生物合成前体增加的需求，同时也依赖强大的pH调节系统来对抗乳酸和碳酸的过度产生。在本综述中，我们介绍了关键的pH调节系统，并整合了将pH控制破坏与生物能量机制相结合的策略的最新进展。我们讨论了在快速生长的肿瘤中利用“代谢灾难”导致急性细胞死亡的可能性。

原文链接：

Disrupting proton dynamics and energy metabolism for cancer therapy