A discovery led by OHSU was made possible by years of study conducted by University of Portland undergraduates.

Scientists have discovered a natural compound that can halt a key process involved in the progression of certain cancers and demyelinating diseases—conditions that damage the protective myelin sheath surrounding neurons, such as multiple sclerosis (MS).

A study published in the Journal of Biological Chemistry identified a plant-derived flavonoid called sulfuretin as an inhibitor of an enzyme linked to both MS and cancer. The research, conducted in cell models at Oregon Health & Science University, demonstrated that sulfuretin effectively blocked the enzyme’s activity. The next phase of research will involve testing the compound in animal models to evaluate its therapeutic potential, effectiveness, and possible side effects in treating cancer and neurodegenerative diseases like MS.

A Potentially Wide-Reaching Treatment

“We think this is a drug that could have impact in a lot of different areas,” said Larry Sherman, Ph.D., professor in the Division of Neuroscience at OHSU’s Oregon National Primate Research Center.

The researchers found that sulfuretin, along with a pair of synthetic compounds that were also tested in live cells, inhibited the activity of a particular type of enzyme known as a hyaluronidase, which naturally degrades hyaluronic acid. That’s important because when hyaluronic acid is broken down into fragments, it is known to cause problems in at least two ways:

• Forestalls myelin repair: It prevents the maturation of oligodendrocytes, which are cells that produce myelin. Myelin is the protective sheath covering each nerve cell’s axon — the threadlike portion of a cell that transmits electrical signals between cells. Damage to myelin is associated with MS, stroke, brain injuries, and certain forms of dementia. In addition, delay in myelination can affect infants born prematurely, leading to brain damage or cerebral palsy.
• Allows cancer cells to proliferate: In cancerous tumors, hyaluronidase activity can allow cancer cells to proliferate unchecked by normal cellular death. “Now we have an inhibitor that could actually stop that,” said Sherman, who is also a professor of cell, developmental, and cancer biology in the OHSU School of Medicine.

The new research focuses on inhibiting a specific type of hyaluronidase known as cell migration-inducing and hyaluronan-binding protein, or CEMIP.

In addition to MS and cancer, CEMIP is implicated in a range of disorders, including osteoarthritis, skin infections, brain injury caused by heavy alcohol use, and possibly other neurodevelopment disorders, including Alzheimer’s disease. The study indicates its activity appears to be inhibited by sulfuretin.

Molecules in flowers

The discovery came after years of undergraduates painstakingly screening plant compounds in the lab of co-author Angela Hoffman, Ph.D., a longtime and now-retired professor of chemistry at the University of Portland.

“Over the years, her students have been grinding up these flowers, extracting molecules, and testing to see if any of them blocked hyaluronidase activity,” Sherman said. “Finally, a couple of years ago, they found a compound that was promising.”

Alec Peters, a graduate student in Sherman’s lab at OHSU, found that this compound blocked CEMIP activity in a tumor cell line and in oligodendrocyte progenitor cells. Oligodendrocytes generate myelin.

Hoffman, a nun and chemistry professor who earlier this year retired from the University of Portland after 35 years to lead her convent, began collaborating with Sherman a decade ago. Over that time, she said, hundreds of undergraduate students worked on breaking down dozens of plants to their molecular essence and then testing to see whether any of the compounds worked to neutralize CEMIP.

The new publication validates the students’ diligent work over many years, she said.

“Directing the students to be able to do this kind of research helps them in their careers,” Hoffman said. “This discovery could be useful for Alzheimer’s or other neurodegenerative conditions. As long as the underlying problem relates to hyaluronic acid being broken apart, this could be helpful for people.”

Reference: “Distinct chemical structures inhibit the CEMIP hyaluronidase and promote oligodendrocyte progenitor cell maturation” by Alec Peters, Fatima Banine, Kanon Yasuhara, Angela Hoffman, Prashant K. Basappa, Lily Metri, Ava Gunning, Jake Huffman, Clinton C. VanCampen, Stephen A. Shock and Larry S. Back, 24 October 2024, Journal of Biological Chemistry.
DOI: 10.1016/j.jbc.2024.107916

The research was supported by the National Institutes of Health, grant award P51 OD011902 for the operation of the Oregon National Primate Research Center at OHSU; Congressionally Directed Medical Research Programs grant award MS160144; the National Multiple Sclerosis Society, grant award RG 4843A5/1; the National Institute of Neurological Disorders and Stroke of the NIH, grant award NS054044; and the National Institute of Alcohol Abuse and Alcoholism of the NIH, grant award P60AA010760.