Paper describing piperlongumine anticancer activity retracted

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.

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.”

“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.”