Breakthrough cancer drug slows inflammation linked to heart disease
[June 12, 2023: Staff Writer, The Brighter Side of News]
Experiments showed that the drug saracatinib reduced this inflammation signaling by more than 90% in human blood samples and diseased tissue samples. (CREDIT: Creative Commons)
In a major leap forward in our ongoing fight against heart disease, a groundbreaking study led by NYU Grossman School of Medicine has discovered that a potential treatment for cancer, lung, and Alzheimer's disease may also be able to hinder the progression of atherosclerosis, a condition that is a primary driver of heart disease.
Atherosclerosis is a disease where fatty deposits accrue in blood vessels, gradually hardening into plaques. This build-up not only blocks blood flow, potentially causing heart attack or stroke, but also triggers misplaced immune reactions, referred to as inflammation. The study's findings, which are set to be published in Nature Cardiovascular Research, shed new light on these processes.
The researchers established that plasma, the liquid component of blood, from patients with atherosclerotic disease set off an unusually high inflammatory signal in blood immune cells. Saracatinib, the experimental drug in question, was then found to dramatically lower this inflammation signaling, reducing it by more than 90% in human blood samples and diseased tissue samples.
"Our findings provide new insight into the inflammatory mechanisms in atherosclerosis and suggest for the first time that saracatinib may offer an effective therapy in cases where standard therapy, in the form of statins, fails to help,” stated study co-lead author Letizia Amadori, PhD, a senior research scientist at NYU Langone Health.
The typical prescription for reducing harmful fats in the blood is statins. Despite their efficacy in decreasing plaque deposits, persistent inflammation remains a problem for many patients, who continue to face a high risk for heart attacks. The underlying causes of this stubborn immune response are not fully comprehended, and anti-inflammatory treatments have often proven ineffective in patient studies.
The research team scrutinized blood samples from 34 men and women diagnosed with atherosclerotic cardiovascular disease (ASCVD), who were all on statins. These were compared with samples from 24 healthy donors. The focus of the study was narrowed down to saracatinib by investigating 4,823 genes, including 277 already known to be implicated in inflammation and the production of proteins that instigate a chronic immune response.
Amadori noted that the team theorized that if a particular drug could inhibit all these molecules from being synthesized, it would be able to mitigate the immune response. Instead of endeavoring to formulate a new drug from the ground up, the researchers utilized a database of pharmaceuticals already approved or being tested for other uses.
Experimental design. PBMCs and plasma were isolated from peripheral venous blood of patients with ASCVD (n = 9 biologically independent samples, 5 men). Healthy plasma was isolated from healthy donors (n = 9 biologically independent samples). (CREDIT: Nature Cardiovascular Research)
This investigation led them to the Library of Integrated Network-Based Cellular Signatures from the National Institutes of Health. This repository holds hundreds of thousands of test results, showing the effects of various molecules, signaling proteins, and genetic alterations on human cells.
Saracatinib emerged as a promising candidate because it was shown to reverse the expression of target genes — the process of genes being activated to synthesize proteins. The authors then trialed it in human cells, diseased tissue, and animal models to ascertain whether it could halt, retard, or reverse the inflammation instigated by ASCVD.
Heat map of mass cytometry data, ordered by stimulatory plasma condition and immune cell types, highlights the activation of specific intracellular markers in monocytes and CD1c+ DCs in response to plasma from patients with atherosclerosis (athero; n = 20 biologically independent samples, 10 men) or healthy plasma (n = 10 biologically independent samples). (CREDIT: Nature Cardiovascular Research)
Remarkably, saracatinib was found to block gene activity that manufactures inflammatory proteins like interleukin-1 beta and interleukin-6, both of which sustain ASCVD’s immune reactivity. An inhibitor of interleukin-1 beta was previously shown to effectively stave off heart attacks in an earlier trial. The drug also promoted genes known to produce proteins that assist in breaking down plaque deposits by moving fat away from the arteries.
Continuing trials in rabbits demonstrated that saracatinib diminished plaque-based inflammation by about 97% compared to untreated animals. Meanwhile, in mice, the therapy resulted in up to an 80% decrease in cells connected to inflammation in plaques, and shrunk plaque deposits by between 48% and 70%, contingent on the dosage of the medication, according to Amadori.
Heat map of mass cytometry data, ordered by immune cell types, highlights the activation of specific intracellular markers in unstimulated PBMCs from patients with atherosclerosis (no plasma athero PBMCs; n = 10 biologically independent samples, 5 men) versus unstimulated PBMCs from healthy donors (no plasma healthy PBMCs; n = 5 biologically independent samples). (CREDIT: Nature Cardiovascular Research)
Chiara Giannarelli, MD, PhD, the study's senior author, emphasized the potential of their innovative approach: “Our reverse-engineering method of finding new uses for old drugs can in theory be harnessed to uncover therapies for practically any disease that involves inflammation. Since these chemicals have already been tested for safety, this technique offers a swift and cost-effective approach to pharmaceutical development.”
Giannarelli, who is an associate professor in the Departments of Medicine and Pathology at NYU Langone, shared that the study team is planning to employ their protocol to delve into possible treatments for other inflammatory conditions associated with ASCVD, such as rheumatic arthritis or type 2 diabetes.
However, Giannarelli also issued a word of caution, stating that while saracatinib shows promise, it must still undergo rigorous clinical testing to ensure its efficacy in patients. With further study and development, this potential new weapon in the fight against heart disease could save countless lives in the future.
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