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Showing posts with label aspirin - AMPK. Show all posts
Showing posts with label aspirin - AMPK. Show all posts

Wednesday, 1 August 2012

Asprin's 'double hit' on bowel cancer

Ref: Asprin's 'double hit' on bowel cancer

reposted from:
crabsallover highlights, key points, comments / links.


Asprin's 'double hit' on bowel cancer
31 May 2012
Aspirin kills cancer cells by controlling two key processes that influence energy use in cells and could explain how aspirin can prevent bowel cancer.

The research is published in Gastroenterology.

Cancer Research UK-funded scientists have found that aspirin switches off mTOR (mammalian Target Of Rapamycin) (wikipedia), a protein that is overactive in bowel cancer cells. 

mTOR plays a part in allowing cancer cells to produce excess proteins causing them to grow faster than they should.

At the same time, aspirin activates another protein, AMPK, which switches on pathways that generate energy but halts other processes in the cell that need energy, including mTOR.

In showing this ‘double hit’, the scientists, based at the University of Edinburgh and Dundee, have unveiled an important mechanism by which aspirin causes cancer cells to destroy themselves.

Researcher Dr Farhat Din, a Cancer Research UK clinician scientist fellow at the University of Edinburgh, said: “There is growing evidence showing that aspirin protects against cancer, but how it brings this about is the subject of much active research. Our new work shows, for the first time, that aspirin is acting on two master regulators of energy in bowel cancer cells and has given us a real insight to the disease.”

mTOR acts in the cell as a central hub that monitors levels of nutrients. By studying cancer cell lines, mice and samples from patients, the researchers were able to show that aspirin was blocking mTOR by measuring levels of proteins that it controls.

There is a growing body of evidence that aspirin can help prevent several cancers, though we know that long term aspirin use can cause harm in some high risk groups.

The scientists’ ultimate aim is to identify targets in the processes involved in cell energy balance in order to develop new drugs that are even better and safer than aspirin at preventing bowel and other cancers.

Dr Din added: “Drugs that target mTOR have been hampered by the cancer’s ability to find alternative ways of using the same pathway, leaving these drugs useless. Using aspirin as a template, we hope to be able to develop drugs that target several parts of the same pathway, enabling us to get around this resistance.”

Professor Nic Jones, Cancer Research UK’s chief scientist, said: “This fascinating research provides an invaluable insight into how aspirin is working in bowel cancer cells. It builds on this team’s earlier work that was the first to demonstrate that aspirin worked to prevent bowel cancer. Cancer Research UK is funding trials and research to find out more about the role aspirin could have in preventing cancer.

“We recommend that anyone considering taking aspirin for cancer prevention should discuss doing so with their GP.”

Source: CRUK

Mechanism of aspirin benefit uncovered (21 Apr 2012)

reposted from:
crabsallover highlights, key points, comments / links.


Mechanism of aspirin benefit uncovered
21 Apr 2012

Secondary source: http://ecancer.org/news/2752
Primary sources:
http://www.sciencemag.org/content/336/6083/918.abstract?sid=0398de80-0e9a-40a9-8c2a-be21090749ea
http://stke.sciencemag.org/cgi/content/abstract/sigtrans;5/225/ec145

Researchers in Canada, Scotland and Australia have discovered that salicylate, the active ingredient in aspirin, directly increases the activity of the protein AMPK (AMP-activated protein kinase), a key player in regulating cell growth and metabolism.

AMPK which is considered a cellular fuel-gauge is switched on by exercise and the commonly used anti-diabetic medication metformin.

The research from scientists at McMaster University, the University of Dundee and the University of Melbourne will be published in today’s issue of the journal Science.

“We’re finding this old dog of aspirin already knows new tricks,” said Dr. Greg Steinberg, a co-principal investigator of the study. “In the current paper we show that, in contrast to exercise or metformin which increase AMPK activity by altering the cells energy balance, the effects of salicylate is totally reliant on a single Ser108 amino acid of the beta 1 subunit.

“We show that salicylate increases fat burning and reduces liver fat in obese mice and that this does not occur in genetically modified mice lacking the beta1 subunit of AMPK,” he said. Steinberg is an associate professor of medicine in the Michael G. DeGroote School of Medicine at McMaster University and the Canada Research Chair in Metabolism and Obesity.

These findings are important as a large clinical trial is currently underway testing whether salsalate (a well-tolerated aspirin derivative), can prevent Type 2 diabetes.

Salicylate, which is derived from willow bark, and is the active ingredient in aspirin, is believed to be one of the oldest drugs in the world with first reports of its use dating back to an Egyptian papyrus in 1543 BC.

An anti-inflammatory drug first used as a painkiller more than a century ago, aspirin is now given to people at risk of heart attacks and strokes as well as patients with vascular disease. McMaster scientists played a key role in that previous research.

Three studies published last month in the medical journal The Lancet reported that taking an aspirin every day may significantly reduce the risk of many cancers and prevent tumors from spreading. The unanswered question was how this anti-cancer benefit occurs.

With many recent studies showing that metformin may be important for cancer prevention the authors’ study raise the interesting possibility that aspirin may also be working in a similar manner; however, further studies are needed as the concentrations of salicylate used in the current study were higher than the cancer trials. Nonetheless, the researchers’ results show the one thing that salicylates and metformin hold in common is their ability to activate AMPK.

Source: McMaster University

Saturday, 21 April 2012

Aspirin activates AMPK enzyme involved in cancer

Refs
1) Science Abstract: http://www.sciencemag.org/content/early/2012/04/18/science.1215327.abstract
2) New Scientist: http://www.newscientist.com/article/dn21718-clues-to-aspirins-anticancer-effects-revealed.html


Why is salicylate (aspirin) an anti-cancer treatment?  Grahame Hardie at the University of Dundee, UK, applied salicylate to cultured human cells derived from the kidney. He found that the drug activated AMP-activated kinase AMPK, an enzyme involved in cell growth and metabolism that has been found to play a role in cancer and diabetes.

Co-author Greg Steinberg of McMaster University in Hamilton, Ontario, Canada, then tested high doses of salicylate on various types of mice. He found that those engineered to lack AMPK did not experience the same metabolic effects from salicylate as seen in mice with AMPK.

Salicylate, in a form called salsalate, has also shown promise as a treatment for insulin-resistance and type 2 diabetes. Those effects, however, appear not to be governed by AMPK. When insulin-resistant mice lacking AMPK were given salicylate, they showed the same improvement in blood glucose levels as normal mice.

The finding potentially separates aspirin's pain-relieving effects from its cancer protection, paving the way for new anti-cancer drugs that have fewer side-effects than aspirin. The next step will be to test salicylate directly in mouse models of cancer, and to see whether AMPK remains important in mediating an anti-cancer effect.

Journal reference: Science, DOI: 10.1126/science.1215327