Drug trodusquemine has weight loss benefits and trials for treating breast cancer, diabetes and heart disease

A new mouse study has shown that the drug trodusquemine can melt away the accumulated arterial plaques that lead to heart attacks and strokes. Atherosclerosis is the number one killer in the world.
Cardiovascular disease (CVD) is a general term used to describe all the conditions affecting the heart and blood vessels and is responsible for almost a third of deaths worldwide.

* the drug is being trialled for treating breast cancer and diabetes has been shown to ‘melt away’ the fat inside arteries that can cause heart attacks and strokes.

All humans have some level of atherosclerosis, regardless of lifestyle and diet. As you age, you start to develop fatty deposits inside your arteries. If you live long enough, these deposits will become a problem.

A research team from the University of Aberdeen showed that a single dose of trodusquemine was able to completely reverse the effects of the disease in just a single dose in mouse models of heart disease.

The model mice with atherosclerosis had less plaque in their arteries when they had regular doses of trodusquemine or just a single dose. The drug works by blocking an enzyme called tyrosine-protein phosphatase non-receptor type 1 (PTP1B), which is normally elevated in people with obesity, diabetes and inflammatory conditions, such as sepsis, allergic lung inflammation, and diabetic foot ulcers.

The researchers discovered that blocking PTP1B also stimulated the protein AMP-activated protein kinase (AMPK). This is one of the central regulators of cellular and organismal metabolism in cells, and it is activated when intracellular ATP (cell energy) lowers.

Trodusquemine is currently in phase 1 trials for breast cancer, but this is the first time the drug has been tested in animal models of atherosclerosis.

Clinical Science – Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR−/− mouse model of atherosclerosis

Abstract

Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with type 1 or type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance, due to impaired insulin receptor (IR) signalling. Here, we demonstrate that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR prevents and reverses atherosclerotic plaque formation in an LDLR−/− mouse model of atherosclerosis. Acute (single dose) or chronic PTP1B inhibitor (trodusquemine) treatment of LDLR−/− mice decreased weight gain and adiposity, improved glucose homeostasis and attenuated atherosclerotic plaque formation. This was accompanied by a reduction in both, circulating total cholesterol and triglycerides, a decrease in aortic monocyte chemoattractant protein-1 (MCP-1) expression levels and hyperphosphorylation of aortic Akt/PKB and AMPKα. Our findings are the first to demonstrate that PTP1B inhibitors could be used in prevention and reversal of atherosclerosis development and reduction in CVD risk.

Atherosclerosis is now well regarded as a chronic low-level inflammatory disease accompanied by a failure to initiate anti-inflammatory signalling, thereby preventing successful engagement of pro-resolution mechanisms and a return to tissue homeostasis. In contrast with previous therapies, including those which inhibit pro-inflammatory signalling, current research is focusing on the promotion from pro-inflammation to pro-resolution, as a means to reduce atherosclerotic plaque development, as well as other chronic inflammatory pathologies . Our study revealed a decrease in MCP-1 expression in trodusquemine-treated mice, suggesting that PTP1B inhibition led to a less pro-inflammatory environment. Furthermore, in our model where PTP1B deletion was myeloid specific, these mice exhibited a decrease in pro-inflammatory IL-6 and TNFα, and an increase in pro-resolution IL-10. Finally, a recent study by Zhu et al. found that IL-10 stimulation of AMPKα phosphorylation and subsequent downstream PI3K/Akt/mTORC1 signalling was critical for eliciting the anti-inflammatory properties of this cytokine. Therefore collectively, these data suggest that PTP1B inhibition may contribute in the switch from pro-inflammation to pro-resolution signalling, via IL-10/AMPKα mechanism.

In conclusion, we demonstrate that global pharmacological inhibition of PTP1B, in addition to its anti-diabetic and weight loss benefits, resulted in both the reduction and reversal in atherosclerotic plaque formation under obesogenic conditions (as achieved by chronic and a single dose exposure, respectively). This was achieved via an IR-independent pathway, and instead engaged Akt/AMPKα signalling to promote a decrease in pro-inflammatory environment. Hence our data strongly suggest that PTP1B inhibitors may be used in pathologies other than type 2 diabetes and that those currently in pre-clinical trials, could be repurposed to target chronic inflammatory pathologies, such as atherosclerosis and help to reduce CVD risk.

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