A cancer drug that's in the final stages of clinical trials could be repurposed as a potential therapeutic strategy for inflammatory diseases, scientists at the University of Cambridge reported.
A study in the Journal of Clinical Investigation identified a molecule that plays a key role in triggering overactive innate immune system reactions to perceived threats, triggering an inflammatory response.
The researchers, from the Victor Phillip Dahdaleh Heart and Lung Research Institute at Cambridge, explained that unabated activation of one of a family of nucleotide-binding and leucine-rich repeat (NLR) genes, a pyrin domain-containing 3 (NLRP3) inflammasome, is already known to be linked with the pathogenesis of various inflammatory disorders.
They demonstrated that a molecule called polo-like kinase 1 (PLK1) was involved in promoting NLRP3 inflammasome activation. PLK1 is involved in cell division which, when it goes awry, can lead to runaway cell division and the development of tumours. This has prompted research into drugs that inhibit PLK1 activity as a potential cancer treatment.
At least one such drug is currently in phase three clinical trials.
However, PLK1 is also involved in other processes, including helping to organise microtubule cytoskeletons. These behave like "train tracks" inside the cell, the researchers explained, allowing important materials to be transported from one part of the cell to another.
Molecule Involved With Inflammasome Activation
The team demonstrated that PLK1 was involved with NLRP3 inflammasome activation in macrophages during the interphase portion of the cell cycle. They showed that PLK1 orchestrated the microtubule-organising centre (MTOC) structure and NLRP3 subcellular positioning upon inflammasome activation.
Using in vivo mouse inflammatory disease models, they demonstrated that treatment with a PLK1 inhibitor prevented the runaway inflammatory response, and did so at a much lower dose than would be required for cancer treatment.
The findings could offer hope for the treatment of a range of diseases including gout, heart failure, cardiomyopathy, and atrial fibrillation, according to the scientists, who said they were planning to test using a PLK1 inhibitor against inflammatory diseases in clinical trials.
Senior author Dr Xuan Li, a research fellow at the University of Cambridge, said: "If we can get in the way of the microtubules as they try to organise 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."
Drugs Have Already Passed Safety Trials
She added: "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 minimise delays in meeting clinical and regulatory milestones.
"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."
James Leiper, professor of cardiovascular and metabolic health at the University of Glasgow, and associate medical director of the British Heart Foundation, which funded the study, said: "It's promising that drugs targeting PLK1 — that work by dampening down the inflammatory response — have already been proven safe and effective in cancer trials, potentially helping accelerate the drug discovery process.
"We hope that this 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 could be repurposed."
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