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早上起床就针对GLUT1写了篇博文,就在它刚上科学网头条不久,就见到主笔那篇“饿死”癌细胞新闻报道的人民日报记者赵永新先生给我打招呼的留言,随后又见到颜宁MM在我博文后留言。从他们的口气看,似乎觉得自己说错了什么或做错了什么。其实不然,我认为他们的想法、说法或做法都不算离谱!
我在2000年后曾做过一段时间的抗肿瘤研究,现在手头还有一个肿瘤干细胞的国家级课题,因此我关注肿瘤的"饥饿疗法"不算管闲事,反而我还应该做多点功课,更深入地挖掘一下。这不,刚才随便上网一查,就找到一篇以GLUT1为靶点开发小分子抗癌药物WZB117开展抗肺癌体内外研究的论文,而且早在两年前就发表了。以下是该论文的题目及摘要,其为Open Access,感兴趣者还可以下载、阅读全文。
A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo.
The functional and therapeutic importance of the Warburg effect is increasingly recognized, and glycolysis has become a target of anticancer strategies. We recently reported the identification of a group of novel small compounds that inhibit basal glucose transport and reduce cancer cell growth by a glucose deprivation-like mechanism. We hypothesized that the compounds target Glut1 and are efficacious in vivo as anticancer agents. Here, we report that a novel representative compound WZB117 not only inhibited cell growth in cancer cell lines but also inhibited cancer growth in a nude mouse model. Daily intraperitoneal injection of WZB117 at 10 mg/kg resulted in a more than 70% reduction in the size of human lung cancer of A549 cell origin. Mechanism studies showed that WZB117 inhibited glucose transport in human red blood cells (RBC), which express Glut1 as their sole glucose transporter. Cancer cell treatment with WZB117 led to decreases in levels of Glut1 protein, intracellular ATP, and glycolytic enzymes. All these changes were followed by increase in ATP-sensing enzyme AMP-activated protein kinase (AMPK) and declines in cyclin E2 as well as phosphorylated retinoblastoma, resulting in cell-cycle arrest, senescence, and necrosis. Addition of extracellular ATP rescued compound-treated cancer cells, suggesting that the reduction of intracellular ATP plays an important role in the anticancer mechanism of the molecule. Senescence induction and the essential role of ATP were reported for the first time in Glut1 inhibitor-treated cancer cells. Thus, WZB117 is a prototype for further development of anticancer therapeutics targeting Glut1-mediated glucose transport and glucose metabolism.
利用体外实验抑制肿瘤细胞生长与人体临床应用完全是两回事。这里面至少有两个方面的原因:一是体外评价实验是直接把药物添加在肿瘤细胞株生长的培养基里,而人体口服或注射给药是靠细胞主动吸收,其疗效取决于药物的生物利用度及靶向运输量。二是体外应用时药物是人为强加和被动吸收,而人体应用受到身体的整体调控,并非加了就吸收,也不是加多少吸收多少,更何况细胞存在主动外排机制,可以把药物完全阻挡在细胞以外。另外,用癌细胞移植裸鼠评价抗癌药的疗效也应该很谨慎,因为肿瘤不是原发的,受宿主免疫监控的程度很低,而且裸鼠为免疫缺陷,无法协同药物的抗癌作用,更难以推及到人体。
附:
[30]颜宁 多谢曾老师科普。我自己本来计划着写一篇博客,讲讲Warburg Effect,导致GLUT1在许多癌细胞里面超量表达,以及据此目前的一些GLUT1 inhibitor在抑制特异种类的tumor (RCC)里面的一些进展。不过,这基本成个小综述了,要加很多文献;而我本人自从不做细胞凋亡之后就没再研究癌症,怕出差错,所以慢工出细活。于是就偷懒在微博上写了几句先:
“我再重申一遍,从基础科研到制药,路漫漫其修远。而我在讲述GLUT1的时候强调的是基础研究本身的意义,那么为何会冒出”饿死癌细胞“这种极具噱头的新闻呢?因为我在回答问题的时候说:细胞需要ATP维持生命活动;正常细胞除了葡萄糖,还可以通过氨基酸、脂肪酸等能量物质;而大脑也可以勉为其难地用酮体 ;但是实体瘤因为缺氧,其ATP只得依赖于糖酵解产生的ATP,所以对葡萄糖格外依赖。这也许提供了一个思路,是否可以通过抑制葡萄糖摄取而定点抑制肿瘤细胞生长?可是癌症如此复杂,要研发药物、创造疗法路阻且长。请支持基础研究,在不断的探索跌撞甚至弯路后,也许会成功。如对以上推理有疑义,欢迎讨论。”
天知道我洋洋洒洒说了50分钟,完全与疾病无关;只在回答问题的时候,说了因为有氧代谢和无氧代谢的区别,是否可以在提供其他营养物质维持正常细胞代谢,阻断葡萄糖运输特异饿死癌细胞。”饿死癌细胞“这五个字可能是记者朋友们唯一听懂的:dizzy:就铺天盖地成了新闻了,吓得我都不太敢看新闻。但也不能因此简单说记者没有职业操守,我觉得绝大多数记者是文科出身,碰上我这种不太会科普的人,能听懂的话太少。是我自己缺乏经验,这回学了个大教训。
稍微更正一下颜宁在以上微博中的一个说法:正常细胞与癌细胞代谢的差异并不是前者可以利用氨基酸而后者不能,因为有很多氨基酸都是从糖酵解中间产物转变而来,反过来说就是氨基酸也能通过糖酵解而被利用。两者的本质区别在于:正常细胞需糖量小,因其产能效率高(有氧代谢),而癌细胞耗糖量大,因其产能效率低(无氧代谢)、生长速率高。由此推论,GLUT1抑制剂对正常细胞的影响远远小于癌细胞。
正如颜宁所言,GLUT1与肿瘤的相关文献其实不少,先列出几篇如下:
FASEB J., Vol. 15, No. 6. (1 April 2001), pp. 907-915, doi:10.1096/fj.00-0398com | |
Journal of Biological Chemistry, Vol. 274, No. 29. (16 July 1999), pp. 20281-20286, doi:10.1074/jbc.274.29.20281 | |
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, Vol. 12, No. 11. (November 1999), pp. 1001-1009 | |
Journal of Biological Chemistry, Vol. 284, No. 4. (23 January 2009), pp. 2031-2037, doi:10.1074/jbc.m804776200 | |
Gynecologic Oncology, Vol. 116, No. 1. (29 January 2010), pp. 21-27, doi:10.1016/j.ygyno.2009.10.040 | |
Anticancer research, Vol. 15, No. 6B. (c 1995), pp. 2895-2898 | |
Current Vascular Pharmacology, Vol. 7, No. 4. (01 October 2009), pp. 534-548, doi:10.2174/157016109789043928 | |
Pharmacology & therapeutics, Vol. 121, No. 1. (January 2009), pp. 29-40, doi:10.1016/j.pharmthera.2008.09.005 | |
Brain Research, Vol. 1280 (14 July 2009), pp. 77-83, doi:10.1016/j.brainres.2009.05.017 | |
Journal of Cancer Research and Clinical Oncology, Vol. 136, No. 2. (1 February 2010), pp. 219-225, doi:10.1007/s00432-009-0652-y |
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