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Ethics

Paper describing piperlongumine anticancer activity retracted

Some coauthors dissent from withdrawal of report, for which key findings have been independently confirmed

by Carmen Drahl
July 25, 2018

 

20180725lnp1-papers.jpg
Credit: Nature
The now-retracted piperlongumine work, reproduced from Nature, DOI: 10.1038/nature10167.

The journal Nature has retracted a paper about piperlongumine, a molecule with promising anticancer activity, over the objection of five of the paper’s 14 authors (Nature 2011, DOI: 10.1038/nature10167). The retraction comes after two extensive corrections to the paper (Nature 2012, DOI: 10.1038/nature10789; 2015, DOI: 10.1038/nature15370). Yet independent groups have confirmed piperlongumine’s potential as an anticancer lead compound and research in the area is likely to continue, experts say.

20180725lnp1-piper.jpg

According to the Web of Science citation index, the retracted work has been cited 577 times. The paper generated intense interest because it demonstrated that piperlongumine killed cancer cells over normal cells, says Yubin Ge of Wayne State University, who wasn’t involved in the retracted study but has tested piperlongumine analogs. C&EN covered the piperlongumine finding when it was published. The compound comes from a pepper plant and kills cancer cells by increasing levels of reactive oxygen species.

The earlier corrections involved issues with study methodology, figures, and compliance with animal welfare guidelines. The study’s breach of the latter prompted an editorial from the journal (Nature 2015, DOI: 10.1038/525290a). The retraction notice cites unspecified issues with two other figures describing piperlongumine’s effects on cancer cells. The journal was unable to obtain original data for the two figures. “These issues in aggregate undermine the confidence in the integrity of this study,” the retraction notice states.

Asked to elaborate on the issues in the retraction notice, a Nature spokesperson said that the journal’s policy is not to comment beyond the text of the notice itself. When Nature’s editors, often in consultation with independent reviewers, deem a retraction is appropriate, the journal contacts all authors to seek assent to the retraction and the retraction statement prior to its publication, according to the spokesperson.

In this case, assent and dissent split along institutional lines. Authors affiliated with Broad Institute of MIT and Harvard, including corresponding author Stuart L. Schreiber, agreed with the retraction. One Broad coauthor did not respond. Meanwhile, authors affiliated with Massachusetts General Hospital and Harvard Medical School, including corresponding authors Anna Mandinova and Sam W. Lee, disagreed with the retraction.

Ivan Oransky, cofounder of Retraction Watch, a site that aims to increase transparency and visibility of retractions, says it’s difficult to track assent and dissent to retractions. “What we see most often is a single author objecting to a retraction, or all authors.” So to some extent the split along institutional lines is unusual, Oransky says, though he cautions his dataset is small.

The corresponding authors could not be reached for comment, but their institutions provided statements to C&EN. “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,” says David Cameron, Broad Institute’s director of communications. “Because the particular figures referenced were not generated at the Broad, we are not in a position to discuss them.”

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“Whenever questions or concerns are raised about the scientific integrity of studies conducted at Massachusetts General Hospital, we take them very seriously and work closely with our colleagues at Harvard Medical School to fully investigate the situation in a fair and confidential manner,” a Massachusetts General Hospital spokesperson said in a statement to C&EN. “We are aware that concerns have been expressed about specific figures in the 2011 letter in Nature. It appears that the journal has decided that these concerns warrant retraction, and we respect the publication’s process for making decisions in these matters.”

In the last few years, Lee has retracted two other papers and issued multiple editorial statements, according to Retraction Watch. Mandinova and Lee formed a company called Canthera Therapeutics to commercialize the piperlongumine work, but the company is closed, according to Google Maps.

“Overall piperlongumine displays promising anticancer activity,” says medicinal chemist Zhihui Qin at Wayne State University, who initiated a piperlongumine-related project Ge joined. “I’m very interested to know more about why some authors of this Nature paper agreed to retract the report, and I will track the development of this news.”

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Comments
Jerome Zoeller (July 25, 2018 9:05 PM)
The cinnamide referred to as Piperlongumine in the article is called "Piperlartine" in a recent article by da Nabrego et al in the June 2018 issue of Molecules. The authors describe and document the antitumor properties of this piperidin-4-ene-one amide of trimethoxy cinnamic acid. Experimental details are presented for the preparation of a library of esters and amides of 3, 4, 5 - trimethoxy cinnamic acid. Notable of all screened, the diphenyl methyl ester ( compound 10 ) showed growth inhibition of U87MG cancer cells of IC 50 at 2.6 ug/mL. The Paclitaxel control read IC 50 at 2.12 ug/mL.

It should be noted that a dozen or more reports of cancer cell growth inhibition, apoptosis and/or cell death is reported for new compounds each month. Many are similar in experimental design to this article, with a large library of compounds, tested against about nine cancer cell lines, with a few of the standard antitumor drugs as controls, for three types of antitumor activity. Most of the promising leads are not even considered for Phase I clinical trials on the basis of some very rigid criteria.

7/25/18
Ray Exley, MD (July 26, 2018 12:43 PM)
Even with the best intentions, very well trained investigators, excellent study design and execution and apparently very good data, it is very easy to make a mistake, particularly when "breakthrough" results seem to be represented in the data. These observations are nothing new to seasoned investigators, particularly with high standards for themselves, and their work product.

Congratulations on the corrections, and attempts to improve on the accuracy of the reports. Such corrections are often difficult on many different levels. But, such actions are necessary, when appropriate.

There but for the grace of "god" I would likely gone (many times) and I salute the integrity of those who are trying to do the corrections, and get the conclusions in line with the data, following the best scientific principles.

"God" is not about religion, but about the caprice of nature and research, and trying to get the published reports as correct as possible, to the best scientific standards, often a very difficult task. I salute the many efforts to get it correct, no matter how many revisions (corrections) it takes. Because the attempts demonstrate (I think) integrity which is so often missing in so much of human activity, such as politics, where it is not pursued, it is just a talking point to be cynically exploited for a short term "win", usually ignoring the many longer term negative effects, of not pursuing truth and accuracy.

And, such corrections are necessary for the published information to be trusted, which is a critical part of the attempts to improve the human condition, by the use of scientific methods.

I don't think I have adequately expressed myself, but I think all involved in producing and then correcting the errors deserve a very strong acknowledgement of their integrity, which is so often missing in many fields of human endeavor.

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