Nature 撤稿：胡椒提取物抗癌有问题 诸平 Abstract Malignant transformation, driven by gain-of-function mutations in oncogenes and loss-of-function mutations in tumour suppressor genes, results in cell deregulation that is frequently associated with enhanced cellular stress (for example, oxidative, replicative, metabolic and proteotoxic stress, and DNA damage) 1 . Adaptation to this stress phenotype is required for cancer cells to survive, and consequently cancer cells may become dependent upon non-oncogenes that do not ordinarily perform such a vital function in normal cells. Thus, targeting these non-oncogene dependencies in the context of a transformed genotype may result in a synthetic lethal interaction and the selective death of cancer cells 2 . Here we used a cell-based small-molecule screening and quantitative proteomics approach that resulted in the unbiased identification of a small molecule that selectively kills cancer cells but not normal cells. Piperlongumine increases the level of reactive oxygen species (ROS) and apoptotic cell death in both cancer cells and normal cells engineered to have a cancer genotype, irrespective of p53 status, but it has little effect on either rapidly or slowly dividing primary normal cells. Significant antitumour effects are observed in piperlongumine-treated mouse xenograft tumour models, with no apparent toxicity in normal mice. Moreover, piperlongumine potently inhibits the growth of spontaneously formed malignant breast tumours and their associated metastases in mice. Our results demonstrate the ability of a small molecule to induce apoptosis selectively in cells that have a cancer genotype, by targeting a non-oncogene co-dependency acquired through the expression of the cancer genotype in response to transformation-induced oxidative stress 3 , 4 , 5 . 《 自然》 （ Nature ） 2011 年发表了一篇论文描述从胡椒中提取的一种化合物—— 荜茇酰胺（ Piperlongumine ）， 似乎可以杀死癌细胞，但健康细胞不会受到伤害 , 使得其受到关注。不仅吸引了许多 媒体 （ caught the media’s eye ） 的注意 ，同时也吸引了跟风 研究者的眼球， 继续研究此化合物（ piperlongumine ）对癌症的影响 , 以 PubMed 数据库为例，相关研究成果数量明显增加。 图 1 荜茇酰胺（ Piperlongumine ）相关研究成果的数量变化 The compound, piperlongumine, comes from the Indian long pepper plant. 但自从 2011 年的相关研究结果 出现时 , 研究人员就 对一些图 有疑虑（ concerns about some of the figures ） —— 包括一个显示小鼠巨大肿瘤 , 建议他们在研究过程中经历了不合理的痛苦。《自然》杂志编辑部通过 2012 年 和 2015 年 发布两个漫长的调整通知对此作出回应，还有 一篇社论 也 承认动物可能 “ 比最初允许经历更多的痛苦和折磨 ,” 但不会导致撤稿 , 结果仍然是 “ 有效的和有用的。 ” 然而，几年过去了，到 2018 年 7 月 25 日，《自然》杂志编辑部公布了 简短的撤稿通知 : This Letter is being retracted owing to issues with Fig. 1d and Supplementary Fig. 31b, and the unavailability of original data for these figures, which raises concerns regarding the integrity of the figures. Nature published two previous corrections related to this Letter. These issues in aggregate undermine the confidence in the integrity of this study. 大致意思是说，此快报被收回由于图 1 d 和补充图 31 b 存在问题 , 而且这些图形的原始数据是无效用的 , 这引发了对于所有图形完整性的担忧。尽管《自然》杂志之前发表过两次相关修正，但总体而言这些问题破坏了本研究的完整性。 撤稿通知中解释道 ,14 位作者当中有 4 位作者不同意撤稿 , 其中包括第一作者和最后一位作者。根据 科睿唯安 （ Clarivate Analytics’ Web of Science ）统计，撤稿论文—— Selective killing of cancer cells by a small molecule targeting the stress response to ROS 已经被引用 577 次 , 使其已经成为 “ 高被引论文 ”, 这意味着它在 2011 年出版的所有论文中被引频次是排名在前 1% 的。在 2015 年 9 月发表校正意见以来它已经被引用了 257 次。 近年来，这次被撤稿论文署名中的最后一位作者 , Sam W. Lee 已经 收回了另外两篇论文。这本身就是一个不祥之兆。 更多细节请注意浏览相关报道 ： All retractions are considered on a case-by-case basis, and decisions about whether to retract are made by Nature’s in-house editors, who may seek advice from independent peer-reviewers. Following this process, if the editors deem that a retraction is appropriate, all authors are contacted to seek their assent to the retraction and the retraction statement. Following this, the retraction notice will be published, and any dissenting authors noted in the text of the published version. More information about our retraction policy is available on our website: https://www.nature.com/authors/policies/corrections.html . We take all issues related to animal welfare very seriously and should we become aware of any breach of our policies in any published paper, we would follow an established process to investigate the issues. More details about Nature’s policies for papers that report experiments with animals are outlined in this editorial: https://www.nature.com/news/protection-priority-1.18354 . When we asked for more specifics about what happened with this particular paper, the spokesperson referred us to the retraction notice: The issues detailed in the retraction notice do not relate to the previous concerns regarding animal welfare, although all these issues in aggregate undermine the confidence in the integrity of this study. One reader forwarded us correspondence with the journal dating back to June 2016, in which he raised concerns that supplementary figure 31 contained manipulated images. We’re also trying to find out more information about why the authors were split in their agreement over the retraction. We contacted coauthor Stuart Schreiber to ask why he agreed with the retraction, and whether it has any impact on a patent related to compounds for cancer therapy, which cites the now-retracted paper ; he said he was traveling, and forwarded us to David Cameron, spokesperson for the Broad Institute of MIT and Harvard. Cameron told us: Although the scientific conclusions of the paper appear sound and its key findings have been extended by other investigators in independent publications, in an abundance of caution all authors who contributed experiments at the Broad Institute of MIT and Harvard support the Nature editors’ recommendation to retract the paper. Because the particular figures referenced were not generated at the Broad, we are not in a position to discuss them. We emailed co-authors Mandinova and Lee , who co-founded a company around the technology described in the paper — and disagreed with the retraction — but have not received a response. Mandinova and Lee have also filed patents together, including one from 2012 that mentions piperlongumine . Lee — based at Massachusetts General Hospital — has retracted two papers — a Molecular Cell paper in 2013 due to figure duplication and a Journal of Biological Chemistry paper in 2015 , citing “manipulated” data in a figure. He’s also issued at least one other mega-correction , and last year received an expression of concern on another 2011 paper, noting “credible concerns” about the data and conclusions .
研究进展： http://news.sciencenet.cn/htmlnews/2010/8/235675.shtm 绿茶中茶多酚可显著提高抗癌药物疗效 信息分析结果： http://www.gopubmed.org/web/gopubmed/1?WEB088zlw1jrq6luI1mI35I00h001000j100300.y 1,404 documents semantically analyzed 1 2 Top Years Publications 2009 131 2007 127 2005 120 2006 117 2008 112 2004 98 2003 95 2002 87 2010 80 2001 70 2000 69 1999 62 1998 50 1997 47 1992 26 1996 21 1995 19 1993 15 1994 12 1991 10 1 2 1 2 3 Top Countries Publications USA 661 Japan 250 China 103 South Korea 43 India 39 Italy 34 Canada 31 Germany 31 Taiwan 27 Australia 20 United Kingdom 19 France 11 Spain 10 Israel 9 Hong Kong 8 Switzerland 7 Netherlands 5 Turkey 5 Sweden 4 New Zealand 4 1 2 3 1 2 3 ... 16 Top Cities Publications Cleveland 62 Tokyo 40 Beijing 33 Madison 31 Santa Clara, USA 27 Los Angeles 26 New York 26 Seoul 25 Saitama 24 Shizuoka 24 Boston 23 Birmingham, USA 21 Detroit 20 Nagoya 18 Chicago 17 Tucson 17 Valhalla 16 Shanghai 15 Taipei 15 Osaka 14 1 2 3 ... 16 1 2 3 ... 22 Top Journals Publications Carcinogenesis 62 Cancer Lett 57 Nutr Cancer 41 Cancer Res 39 Int J Cancer 32 J Nutr 31 Mutat Res-fund Mol M 28 Anticancer Res 21 Clin Cancer Res 21 Cancer Epidem Biomar 19 Biochem Bioph Res Co 16 Jpn J Cancer Res 15 Cancer Prev Res (phila Pa) 14 Biochem Pharmacol 14 Life Sci 13 J Agr Food Chem 13 Int J Oncol 12 Food Chem Toxicol 12 Zhonghua Yu Fang Yi Xue Za Zhi 12 Eur J Cancer Prev 12 1 2 3 ... 22 1 2 3 ... 268 Top Terms Publications Humans 963 Tea 850 Animals 731 Catechin 718 Neoplasms 589 Mice 390 Anticarcinogenic Agents 361 Flavonoids 333 Apoptosis 321 Proteins 312 Antioxidants 300 apoptosis 289 Phenols 280 Cell Line 252 Plant Extracts 247 Cell Line, Tumor 223 African Continental Ancestry Group 207 Cell Proliferation 206 Chemoprevention 203 DNA 198 1 2 3 ... 268 1 2 3 ... 236 Top Authors Publications Mukhtar H 76 Yang C 63 Katiyar S 37 Fujiki H 34 Suganuma M 33 Ahmad N 27 Rath M 25 Lee M 23 Agarwal R 22 Kalinovsky T 21 Niedzwiecki A 21 Roomi M 20 Dou Q 19 Conney A 18 Ho C 18 Adhami V 17 Lou Y 15 Huang M 15 Gupta S 14 Nakachi K 14 1 2 3 ... 236
云无心 发表于 2009-03-17 11:31 3 月 1 日的《新知周刊》刊登了一篇题为《苹果可抗癌，苹果可救命》的文章，介绍了康奈尔大学一位教授最近发表的动物实验，证明苹果可抗癌，最后认为 苹果和苹果皮将会真正成为挽救人性命的宝贝 。客观地说，那项研究结果发表在专业期刊上没有什么问题，但是作为一个结论向公众推荐就非常草率，甚至是相当误导。 首先，这只是一项动物实验。在食品领域，如果动物实验证明一种成分能够致癌，那么就足以判处这种成分死刑。但是要证明一种食物成分有助健康，动物实验只是非常初步的结论。要想把它作为一个结论向公众推荐，至少还需要临床试和统计数据，得出吃多少的量能有多大的效果，以及这个量对于人体健康有没有别的负面作用等等。 许多食品成分的研究进行了几十年，类似这样在动物身上有效的结果比比皆是，甚至临床试验的结果也不少，但是依然不能得到学术界以及主管部门的认可。 2001 年，欧洲有个公司，生产一种叫作 RED NOSE 的饮料。那种饮料的主要成分是葛根和菊花，作用是解酒，他们申请在上市美国的产品包装上印上解酒功能。这项功能的证据一是类似的东西被中国人用来解酒有很悠久的历史，二是哈佛大学等研究机构发表的一些相关的实验结果，甚至还提供了一些机理方面的解释。 FDA 的回复否决了这项申请，理由是：解酒是一种治疗作用，如果要宣称这项功能，那么需要按照药品来对待，从而需要通过药物申请程序。而药物申请程序，就需要大量的实验数据来评估剂量、安全性、有效性等等。哈佛等机构发表的那些研究结果，还远远不足。如果比较苹果可抗癌的这篇文章，可以看出其证据比起葛根解酒还更为初步。 苹果是一种食物，不管是国外的还是中国的法律，都不允许宣传食品具有诊断、治疗、预防疾病的功能。现代科学表已经证实，蔬菜水果对于人体健康有很大的益处。这种益处发生的前提是食谱中的蔬菜水果占较大比重，而不是指望某种神奇的品种。各种蔬菜水果各不相同，它们带给人体的成分也各不相同，但是人体需要所有这些不同的益处。跟药品不同，人们每天所吃的食物总量是有限的，这种吃得多了，那种必然吃得少。比如在苹果抗癌这个例子中，如果真的有人每天吃 6 个苹果去获得较强的抗癌效果，就必然要减少别的食物摄取量。而其它那些食物带来的益处必然减弱，对整体健康而言，这样过于单一的食品可能是不利的。现在的食品科学研究在评估某种食物对健康影响的时候，已经不怎么依赖于这种对照实验，而是要进一步评估这种食物的引入对整个食谱的影响。 我们经常看到保健品或者功能食品说有科学研究表明，甚至列出一大堆科学期刊上的论文。这样的宣传，再加上一些媒体随意地夸大解读这些论文，经常把一般公众唬住。自然的真相就像一头大象，在它面前人类都是盲人。科学研究的结果，就是盲人摸象的记录。哪怕每个人的记录都是真实的，也不能依靠几条记录画出大象来。只有经过许多许多的人，从不同的角度来摸，来记录，然后把所有人的记录汇总起来，才有可能画出足够逼真的大象。 再举一个例子，很多人都听过绿茶防癌的说法。在科学研究期刊上，也确实能够找到大量的这方面的研究。 2004 年有人向 FDA 申请这样的认证：每天饮用 40 盎司的绿茶可以减轻一些癌症的发生风险。虽然有科学证据支持，但是这些证据还不够完善。他们提交了各种学术期刊上的大量研究论文来支持绿茶防癌。在许多人看来，那些论文已经足够权威足够大量来证明第一句话了，但是申请者还是加上了引号里的第二句话以示谨慎。 FDA 在审查了所有的这些证据之后，结论是只有非常有限的可信证据支持绿茶对于乳腺癌和前列腺癌有一定好处，而证明绿茶对其它癌症好处的证据都不够可靠。所以， FDA 最后同意厂家可以使用的表述是一项微弱并且有限的研究没有显示喝绿茶能降低前列腺癌的发生风险，但是另一项微弱并且有限的研究显示能够降低这一风险。基于这些研究， FDA 认为绿茶不大可能降低前列腺癌的风险。对于乳腺癌的表述也大致如此。如果厂家改变上诉完整表述的意思，或者选择性的使用科学研究来推销产品，那么就会受到 FDA 的追究。同时， FDA 也指出，这些决定是基于已有的科学证据，如果有了新的科学证据，可以重新审查改变 FDA 的认证。 如果把苹果抗癌的研究与绿茶防癌的相比，几乎可以忽略不计。我们也可以注意到，那项研究是苹果协会资助的。虽然结果发表在了正规的学术期刊上，可是如果他们要用其结论来帮助推销苹果的话，也会是吃不了兜着走。 (本文发表于《新京报新知周刊》，有删改) -公告： 小姬看片会第七期：飞翔北大
标签: 抗癌
