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所有实体瘤内部的核心癌细胞都处于低氧水平，因此这些癌细胞都依赖分解葡萄糖产生能量的糖酵解代谢过程。这些癌细胞天然生长缓慢，而且对常规抗癌疗法（如化疗）均有耐药性。 2016年5月10日，美国《肿瘤标靶》杂志在线发表美国迈阿密大学、美国卫生研究院、西班牙Llobregat医院Bellvitage生物医学研究所的研究报告，发现一种新型营养疗法可以治疗乳腺癌、黑色素瘤、骨肉瘤。这种新型疗法基于2-脱氧-D-葡萄糖（2-DG）和降胆固醇药物非诺贝特（FF）的联合疗法而开发。 该研究发现，阻断醣酵解过程的“假糖”（如2-DG）可选择性饿死生长缓慢的癌细胞，同时保留正常细胞，而正常细胞利用其他能源（如脂肪和蛋白质）产生能量，因为这些物质处于完全氧化状态。 虽然目前2-DG联合常规化疗药物还处于Ⅰ期临床研究阶段，但是已被证明可以成功抵抗癌细胞，不过化疗产生的严重毒性副作用仍然是一个问题。本研究将2-DG与FF进行联合，FF是一种已经安全用于人类超过40年的药物，可以降低胆固醇和甘油三酯，研究结果表明2-DG联合FF可以在不产生严重毒性副作用的前提下有效靶向作用于肿瘤细胞。 该研究发现，FF联合2-DG可以同时诱发两种应激效应，即能量应激和内质网应激，这两种应激均不能被大部分癌症所克服。由于癌细胞的自由生长及微环境异常，往往要比正常健康细胞面临更多应激。此外，2-DG还会利用癌细胞的特性增加葡萄糖摄入。当2-DG联合FF，就可以有效利用癌细胞应激增加的特点，对癌细胞进行精确狙杀。 因此，这种新型联合疗法可能帮助治疗乳腺癌、黑色素瘤、骨肉瘤，对于后期开发更多有效个体化癌症疗法提供了研究基础和思路。 非诺贝特（FF）对于内科医生是非常熟悉的经典老药，价格非常便宜，而且属于医保乙类药物。 2-脱氧-D-葡萄糖（2-DG）对于兽医也是非常熟悉的经典老药，能够抑制病毒感染、酵母发酵、病菌及肿瘤细胞生长等多种生理药理效应，具有抗病毒、抗菌、抗癌、抗癫痫、抗衰老等作用，可以预防病毒及病原菌感染等，可防止HSV、HIV、流感病毒等病源菌引起的传染病，可治疗疱疹等，主要用于畜禽各种病毒病、免疫抑制病的预防和治疗，也可作为细菌及支原体感染的辅助治疗，在医药及化妆品等行业具有广泛的应用前景，目前国内主要用于禽类和兽类。 Oncotarget. 2016 May 10. [Epub ahead of print] Combining 2-deoxy-D-glucose with fenofibrate leads to tumor cell death mediated by simultaneous induction of energy and ER stress. Liu H, Kurtoglu M, León-Annicchiarico CL, Munoz-Pinedo C, Barredo J, Leclerc G, Merchan J, Liu X, Lampidis TJ. University of Miami, Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USA; National Institutes of Health, Bethesda, MD, USA; IDIBELL (Bellvitage Biomedical Research Institute) L'Hospitalet de Llobregat, Barcelona, Spain. Unregulated growth and replication as well as an abnormal microenvironment, leads to elevated levels of stress which is a common trait of cancer. By inducing both energy and endoplasmic reticulum (ER) stress, 2-Deoxy-glucose (2-DG) is particularly well-suited to take advantage of the therapeutic window that heightened stress in tumors provides. Under hypoxia, blocking glycolysis with 2-DG leads to significant lowering of ATP resulting in energy stress and cell death in numerous carcinoma cell types. In contrast, under normoxia, 2-DG at a low-concentration is not toxic in most carcinomas tested, but induces growth inhibition, which is primarily due to ER stress. Here we find a synergistic toxic effect in several tumor cell lines in vitro combining 2-DG with fenofibrate (FF), a drug that has been safely used for over 40 years to lower cholesterol in patients. This combination induces much greater energy stress than either agent alone, as measured by ATP reduction, increased p-AMPK and downregulation of mTOR. Inhibition of mTOR results in blockage of GRP78 a critical component of the unfolded protein response which we speculate leads to greater ER stress as observed by increased p-eIF2α. Moreover, to avoid an insulin response and adsorption by the liver, 2-DG is delivered by slow-release pump yielding significant anti-tumor control when combined with FF. Our results provide promise for developing this combination clinically and others that combine 2-DG with agents that act synergistically to selectively increase energy and ER stress to a level that is toxic to numerous tumor cell types. KEYWORDS: 2-deoxy-D-glucose; eIF2α; energy stress; fenofibrate; mTOR PMID: 27183907 DOI: 10.18632/oncotarget.9263
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