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Kedar Puvar
At first glance, mushrooms, being immobile and nutritious, seem to be rather unassuming. Why, then, would you want to turn to mushrooms of all things as a source of new medicines? It turns out that they make up for their evolutionary weaknesses with a powerful toolbox of molecular defenses against predators, bacteria, and other harmful events. This is great for these fungi and also people: natural products derived from fungi, including penicillin, often possess unique therapeutic properties.
Today, the study of small molecules and proteins from mushrooms has been growing rather quickly and much work remains to be done. It is estimated that 90% of all mushroom species have yet to be discovered! This idiosyncratic kingdom of life is a real treasure trove of potential medicines. In today’s post we will be putting the spotlight on two interesting examples of potential new anticancer options brought to us by the humble mushroom.
The first compound is a protein called Y3, coming to us from Coprinus comatus, better known as the shaggy ink cap mushroom. In 2017, researchers from the University of Florida at Gainesville found this protein to have some striking properties. First, they discovered that Y3 was very effective at killing leukemia cells. This effect was specific to leukemia, as non-malignant control cells were not affected. Second, Y3 seemed to latch onto the surface of the leukemia cells, suggesting that this interaction likely triggered cell death. In fact, a nontoxic mutant version of Y3 also was unable to bind with the cell surface.
Scientists discovered that Y3 is a lectin, a protein that binds to carbohydrate sequences commonly found on cell surface, using a high-resolution atomic structure of the protein that was solved using X-ray crystallography.
The Florida group also showed that Y3 recognized LDNF, a unique carbohydrate sequence not commonly found in normal human cells. Could it be that Y3’s lethal effects against leukemia cells are linked to the presence of this rare LDNF? We will have to wait for further research to fully establish that link, but if that is the case, then this gives us a new marker for leukemia that allows us to recognize it more easily and also provide a path for rational design of therapeutics that can exploit this signal.
Another fascinating example of a mushroom anticancer compound is called ergosterol peroxide (EP) from the species Ganoderma lucidum, which has been used in traditional Chinese medicine for a long time, and still is today. After discovering that extracts from this mushroom had the ability to kill breast cancer cells in the lab, a collaborative research team from Universidad Central del Caribe and St. Jude Children’s Research Hospital identified three abundant compounds in this extract that exhibited anticancer activity, with EP having the greatest effect. Moreover, it was not toxic to non-malignant cells. How did this compound work? Scientists hypothesize that it generates reactive oxygen species, which damage DNA and cause cell death.
The research team went a step beyond EP, and synthesized several compounds that were based on the overall molecular structure of EP but with some unique modifications, in an attempt to improve their ability to get inside of cells. As predicted, these modified compounds proved to be better at attacking cancer cells and more potent than their predecessor, EP. This is a promising start to evaluating a potential new anti-cancer molecule.
Scientists are turning to a multitude of different sources to find new bioactive compounds. One of the richest such sources is the fungi kingdom, particularly mushrooms. Not only may compounds such as Y3 and EP help us in the fight against cancer, but they are helping us better understand the molecular mechanisms that cause cancer and allow us to perhaps recognize cancer cells better. It won’t be surprising if we continue discovering newer molecules like these in the near future.
Works Discussed:
Kornienko, A., Evidente, A., Vurro, M., Mathieu, V., Cimmino, A., Evidente, M., … Kiss, R. (2015). Towards a Cancer Drug of Fungal Origin. Medicinal Research Reviews, 35(5), 937–967. https://doi.org/10.1002/med.21348
Martínez-Montemayor, M. M., Ling, T., Suárez-Arroyo, I. J., Ortiz-Soto, G., Santiago-Negrón, C. L., Lacourt-Ventura, M. Y., … Rivas, F. (2019). Identification of Biologically Active Ganoderma lucidum Compounds and Synthesis of Improved Derivatives That Confer Anti-cancer Activities in vitro. Frontiers in Pharmacology, 10. https://doi.org/10.3389/fphar.2019.00115
Zhang, P., Li, K., Yang, G., Xia, C., Polston, J. E., Li, G., … Ding, Y. (2017). Cytotoxic protein from the mushroom Coprinus comatus possesses a unique mode for glycan binding and specificity. Proceedings of the National Academy of Sciences, 114(34), 8980–8985. https://doi.org/10.1073/pnas.1706894114
Title Image Sourced From Flickr user petrOlly
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