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X-ray crystallography uncovers anticancer properties of Indian pepper plant
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Researchers have identified the chemical process behind the anticancer properties of piperlongumine, the compound found in the spicy Indian pepper plant.
They used X-ray crystallography to solve molecular structures that show how the compound transforms after ingested into cells.
Once ingested, piperlongumine converts to hPL, an active drug that mutes the glutathione S-transferase P1 (GSTP1) gene, which produces a detoxification enzyme abundant in tumors.
“We are hopeful that our structure will enable additional drug development efforts to improve the potency of [piperlongumine] for use in a wide range of cancer therapies,” Kenneth Westover, MD, assistant professor of radiation oncology and biochemistry at University of Texas Southwestern Medical Center, said in a press release. “This research is a spectacular demonstration of the power of X-ray crystallography.”
HemOnc Today spoke with Westover about how he became involved in the research of the spicy Indian pepper plant and the implications of the findings on the potential development of cancer therapies.
Question: How did you get involved in research related to the anticancer properties of the pepper plant?
Answer: I found out about the piperlongumine compound from researchers at the Broad Institute and Massachusetts General Hospital when I was a radiation oncology resident in training. The project was unpublished at that point. I was really intrigued by the compound and never forgot about it. When Raj and colleagues published the paper in Nature in 2011, there was an obvious opportunity for structural biology to explain some of the chemistry they had done. We fulfilled that need with this study.
Q: How did you conduct the study?
A : We started by performing X-ray crystallography to understand how the piperlongumine binds to GSTP1. Based on the structure, we were able to make hypotheses that led to other experiments.
Q: What did you learn?
A: We learned that piperlongumine appears to be a pro-drug with respect to its GSTP1 activity. It is in a certain form before entering the cell, and then it changes form upon entering the cell. This change in form appears to be important for how GSTP1 exerts its anticancer activity.
Q: What implications does this knowledge have for drug development and cancer therapies?
A: The data should help the drug development community design new iterations of this compound that are more potent for cancer therapy.
Q: What is X -ray crystallography and how does it work?
A: We take molecules and subject them to conditions that cause them to organize into a crystalline matrix where all molecules are related to each other by symmetry. When crystals are subjected to X-rays, we get a diffraction pattern. The X-ray diffraction pattern is mathematically related to the structure of the molecules that make up the crystal, which allows us to make a 3D model of where all of the atoms in the molecule are located. X-ray crystallography can be used for small molecules and to study very large molecules, such as proteins. Because of the usefulness, precision and high degree of certainty that X-ray crystal structures give us, X-ray crystallography has been the underlying technique leading to multiple Nobel Prizes on a variety of topics.
Q: How common is the method?
A: It is quite common. There are a number of crystallographers and even scientific societies devoted to the technique. Thankfully, the Department of Energy supports facilities that enable this critically important technique.
Q: How else has it been used in cancer research?
A: It has been used to study all manners of cancer-associated proteins, including signaling proteins like RAS and kinases, and many other macromolecules that support the cancer state. Many of these proteins have been crystallized and structures determined to design drugs or understand how these proteins work. The technique can be applied to a wide range of problems.
Q: What other types of unanswered questions in cancer research might this technique be used to answer?
A: There are so many. It is such a generalizable technique. You can take almost any biological process and get valuable information from structural study. Being able to see — having vision — on an atomic scale has a number of advantages.
Q: Is this a technique we could expect to hear more about in the near future?
A: Yes. In 2014, we celebrated the International Year of Crystallography, marking the centennial of the Nobel Prize of Max Von Laue, the first scientist to diffract X-rays with a crystal. X-ray crystallography has been around for a very long time and has contributed in incalculable ways to our scientific understanding of the submicroscopic world. We will continue to get more crystal structures and they will help us understand all sorts of biology, including cancer.
Q: Is there anything else that you would like to mention?
A: Before our study, chemists made a number of compounds related to piperlongumine trying to make the compound better. There are several papers on this. However, their design decisions required a lot of guesswork because they could not see the interaction between the protein and the chemical. With this new structure, it should accelerate progress on piperlongumine research.
References:
Harshbarger W, et al. J Biol Chem. 2017;doi:10.1074/jbc.M116.750299.
Raj L, et al. Nature. 2011;doi:10.1038/nature10167.
For more information:
Kenneth Westover, MD, can be reached at University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390;email: kenneth.westover@utsouthwestern.edu.
Disclosure: Westover reports no relevant financial disclosures.