Chronic inflammation is a leading cause of cancer worldwide. A new study by researchers at the Mass General Cancer Center, a founding member of the Mass General Brigham Health System, reveals that statins (drugs commonly used to lower cholesterol) may block a particular pathway involved in the development of cancer that results from chronic inflammation . Scientists relied on cell lines, animal models, human tissue samples and epidemiological data to study the mechanism by which environmental toxins trigger the initiation of chronic, cancer-prone inflammation in the skin and pancreas. The group’s cellular experiments demonstrated that environmental toxins activate two linked signaling pathways called the TLR3/4 and TBK1-IRF3 pathways.
This activation leads to the production of the protein interleukin-33 (IL-33), which stimulates inflammation in the skin and pancreas that can contribute to the development of cancer. When examining a library of US FDA-approved drugs, the researchers found that a statin, pitavastatin, effectively suppresses IL-33 expression by blocking activation of the TBK1-IRF3 signaling pathway. In mice, pitavastatin suppressed environmentally induced inflammation in the skin and pancreas and prevented the development of inflammation-related pancreatic tumors. In human pancreatic tissue samples, IL-33 was overexpressed in samples from patients with chronic pancreatitis and pancreatic cancer compared to normal pancreatic tissue.
The drug interfered in the activation of the TBK1-IRF3 pathway because it blocks the production of the intermediate geranylgeranyl-pyrophosphate (GGPP), which serves for the correct anchoring of many proteins to the cell membrane in order to function correctly. One of these is the upstream kinase TBK-1. Therefore this molecular pathway could be targeted by pitavastatin in other clinical conditions in which it is hyper-functioning and causes disease (e.g. the excessive production of interferon-beta which occurs in viral encephalitis, some forms of leukemia and tumors where the mutation in the K-Ras gene exists). Additionally, in analyzes of data from more than 200 million electronic health records in North America and Europe, pitavastatin use was linked to a significantly reduced risk of chronic pancreatitis and pancreatic cancer.
The findings demonstrate that blocking IL-33 production with pitavastatin may be a safe and effective preventative strategy to suppress chronic inflammation and the subsequent development of certain tumors. Pancreatitis is a worrisome clinical condition, which result lethal in at least 20% of cases when in acute settings. Scientists will have to ascertain which other forms of cancer this drug is effective on and whether it has molecular targets responsible for this effect. In fact, its structure resembles that of certain protein kinase inhibitors; furthermore, it was found to inhibit the MARCH5 enzyme at the level of immune cells. This may also explain why it was pitavastatin and not other better-known statins that were noted for these effects.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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