Researchers discover mechanism behind immunosuppressive effects of drugs used to treat autoimmune disorders and cancers

November 24, 2016, University of Texas at Arlington
Credit: University of Texas at Arlington

Biochemists at The University of Texas at Arlington have demonstrated the mechanism behind how thiopurine drugs suppress immune response.

This knowledge could lead could lead to an improvement of those drugs, which are commonly used to treat autoimmune disorders and cancers, but are also associated with side effects like and hypertension.

"Up to now, no one has known exactly how the thiopurine immunosuppressive process works," said Jongyun Heo, associate professor of chemistry and leader of the study published in the Journal of Biological Chemistry. "We are hoping that this discovery also creates an opportunity to improve thiopurine drugs and to design new chemotherapeutic agents for ."

The researchers showed that thiopurine drugs bond with Rac1 proteins within the immune system's T cells with a disulfide bond. This bond deactivates the protein and suppresses the cell's .

This new study also demonstrated that thiopurine can also form bonds with other proteins in T cells like RhoA, which is involved in vascular functions, and Cdc42, whose aberrant activation can result in .

"It is now important to investigate whether thiopurine directly induces vascular or heart diseases through bonds with these other proteins, to alleviate potential cytotoxicities and side effects," Heo added. "There is also a potential opportunity to take advantage of this knowledge to develop new tools to fight cancer by stopping cancer metastasis by inactivating the proteins involved in cell proliferation."

Heo's co-author on the paper was Jin-Young Shin of the Biologics Research Division of the National Institute of Food and Drug Safety Division of South Korea. The work was supported through a National Institutes of Health grant.

The researchers used T cell-based oxidation reduction biochemistry approaches to examine the mechanistic features of thiopurine mediated Rac1 inactivation. These features, as explained in the diagram, detail a precise mechanism for this process.

Fred MacDonnell, UTA chair of chemistry and biochemistry, underlined the importance of this research in the context of UTA's increasing focus on health and the human condition within the Strategic Plan 2020: Bold Solutions|Global Impact.

"Large numbers of patients dependent on thiopurine drugs could potentially benefit from improvements in the or developed on the basis of this discovery," MacDonnell said. "Further research could also help improve our tools in the fight against cancer, which would be another important step forward."

Explore further: Thiopurine therapy improves quality of life

More information: Jin-Young Shin et al. Thiopurine Prodrugs Mediate Immunosuppressive Effects by Interfering with Rac1 Protein Function, Journal of Biological Chemistry (2016). DOI: 10.1074/jbc.M115.694422

Related Stories

Thiopurine therapy improves quality of life

March 1, 2010

Patients with inflammatory bowel diseases (IBDs) such as Crohn's disease or ulcerative colitis do perceive a benefit from thiopurine treatment. A report in the open access journal BMC Gastroenterology has demonstrated improved ...

Genetic-screening trial could reduce drug side-effects

June 24, 2011

(Medical Xpress) -- Patients with a range of common inflammatory diseases that also have genetic variations leading to low levels of a particular enzyme in their bodies are at greater risk of suffering side-effects from the ...

Recommended for you

Nucleation a boon to sustainable nanomanufacturing

September 19, 2018

Calcium carbonate is found nearly everywhere, in sidewalk cement, wall paint, antacid tablets and deep underground. Engineers at Washington University in St. Louis have used a unique set of state-of-the-art imaging techniques ...

Greater than the sum of its parts

September 18, 2018

When it comes to designing and optimizing mechanical systems, scientists understand the physical laws surrounding them well enough to create computer models that can predict their properties and behavior. However, scientists ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.