近日，刊登于国际杂志Oncotarget上的一项研究论文中，来自迈阿密大学米勒医学院的研究人员通过研究开发了一种新型无毒疗法来治疗多种类型的癌症；这种新型疗法基于2-脱氧葡萄糖(2-Deoxy-D-glucose，2-DG)和胆固醇药物非诺贝特的组合性疗法而开发。
研究者Theodore Lampidis说道，在所有实体瘤的内部核心中发现的癌细胞中的氧气水平都异常低，而正因为如此，这些癌细胞都依赖于糖酵解过程，糖酵解是一种通过分解葡萄糖来产生能量的代谢过程，这些癌细胞天生生长缓慢，而且其对常规的癌症疗法均产生耐药性，比如放疗和化疗等。
本文研究中，研究人员发现，阻断醣酵解过程的“假糖”，比如2-脱氧葡萄糖就会有选择性地饿死生长缓慢的癌细胞，同时会保留正常细胞，而正常细胞是利用其它能源来产生能量，比如脂肪和蛋白质，因为这些物质处于完全氧化状态。尽管目前该项研究还处于I期临床试验阶段，但2-脱氧葡萄糖结合常规抗癌药物的联合疗法被证明可以成功抵御癌细胞，而化疗产生的毒性副作用仍然是一个问题；本文研究中，研究人员就将药物非诺贝特同2-脱氧葡萄糖进行结合，药物非诺贝特是一种已经安全应用超过40年的用于降低人类机体胆固醇和甘油三酯水平的药物；研究结果表明，非诺贝特同2-脱氧葡萄糖的结合可以在不产生毒性副作用的前提下有效靶向作用肿瘤细胞。
研究者发现，当非诺贝特和2-脱氧葡萄糖的特殊结合就可以同时诱发两种压力效应，即能量压力和内质网应激压力，这两种压力均不能被大部分癌症所克服。由于癌细胞的自由生长及异常的微环境所致，其往往要比正常健康细胞面临更多压力，此外，2-脱氧葡萄糖还会利用万能的癌细胞特性即便增加葡萄糖摄入，当同非诺贝特结合后，组合性疗法就可以有效利用癌细胞的第二个特点即增加压力，来对癌细胞进行精确狙杀。
最后研究者Lampidis说道，我们认为这种新型的组合性疗法或可帮助治疗多种类型的癌症，对于后期开发更多有效的个体化癌症疗法提供了一定的研究基础和思路。
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Combining 2-Deoxy-D-glucose with fenofibrate leads to tumor cell death mediated by simultaneous induction of energy and ER stress
Huaping Liu1, Metin Kurtoglu2, Clara Lucia León-Annicchiarico3, Cristina Munoz-Pinedo3, Julio Barredo4, Guy Leclerc4, Jaime Merchan5, Xiongfei Liu1, Theodore J. Lampidis1
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.