A cancer drug in the final stages of clinical trials may be able to help treat a range of inflammatory diseases including gout, heart failure, cardiomyopathy, and atrial fibrillation, according to scientists at the University of Cambridge.
Their findings are published in the Journal of Clinical Investigation in an article titled, “PLK1 inhibition dampens NLRP3 inflammasome-elicited response in inflammatory disease models.”
“Unabated activation of the NLR family pyrin domain–containing 3 (NLRP3) inflammasome is linked with the pathogenesis of various inflammatory disorders. Polo-like kinase 1 (PLK1) has been widely studied for its role in mitosis,” wrote the researchers. “Here, using both pharmacological and genetic approaches, we demonstrate that PLK1 promoted NLRP3 inflammasome activation at cell interphase. Using an unbiased proximity-dependent biotin identification (Bio-ID) screen for the PLK1 interactome in macrophages, we show an enhanced proximal association of NLRP3 with PLK1 upon NLRP3 inflammasome activation. We further confirmed the interaction between PLK1 and NLRP3 and identified the interacting domains.”
Several of these conditions are characterized by overactivation of a component of the innate immune response known as an inflammasome, specifically, NLRP3.
Scientists at the Victor Phillip Dahdaleh Heart and Lung Research Institute at Cambridge have found a molecule, PLK1, that helps NLRP3 respond.
Xuan Li, PhD, from the department of medicine at the University of Cambridge and the study’s senior author, said: “If we can get in the way of the microtubules as they try to organize themselves, then we can in effect slow down the inflammatory response, preventing it from causing collateral damage to the body. We believe this could be important in preventing a number of common diseases that can cause pain and disability and in some cases can lead to life-threatening complications.”
PLK1 also plays another important role in the body which may hold the key to developing new treatments for inflammatory diseases.
Scientists have known that PLK1 is involved in cell division, or mitosis, a process that has led pharmaceutical companies to test drugs that inhibit its activity as potential treatments for cancer. At least one of these drugs is in Phase III clinical trials.
When the Cambridge scientists treated mice that had developed inflammatory diseases with a PLK1 inhibitor, they showed that it prevented the runaway inflammatory response— and at a much lower dose than would be required for cancer treatment.
The researchers are currently planning to test its use against inflammatory diseases in clinical trials.
“These drugs have already been through safety trials for cancer—and at higher doses than we think we would need—so we’re optimistic that we can minimize delays in meeting clinical and regulatory milestones,” added Li.
“If we find that the drug is effective for these conditions, we could potentially see new treatments for gout and inflammatory heart diseases—as well as a number of other inflammatory conditions—in the not-too-distant future.”
The researchers hope that their research will open the door for new ways to treat people with heart diseases caused by overactive and aggressive immune responses, and look forward to more research to uncover how this drug could be repurposed.