Identifying new mechanism for aspirin in cancer prevention

In a study published in the journal of Cancer Epidemiology, Biomarkers, and Prevention, Ulrich and her collaborators used a new technique, metabolite profiling, to identify a biochemical pathway previously unknown to be regulated by aspirin. Specifically, the researchers found that aspirin substantially decreases the level of a chemical called 2-hydroxyglutarate in the blood of healthy volunteers and in two colorectal cancer cell lines. This chemical, 2-hydroxyglutarate, is considered a driver of cancer development (known as an oncometabolite) because elevated levels have been found in certain cancers of the blood and brain and several groups are currently studying it as a molecule that promotes tumor formation.

Ulrich says the study adds to the overall evidence that aspirin is important for cancer prevention and points to a new pathway that deserves further study in the context of aspirin. "It is really exciting that aspirin, which can work in colorectal cancer prevention, is now linked to a new pathway that has shown to be relevant for cancer formation."

The first part of the study involved looking comprehensively at the metabolic profiles from the blood of 40 individuals who had taken aspirin for 60 days. The design was rigorous, with participants each having a phase with and without aspirin. More than 360 metabolites, or small molecule chemicals such as sugars, amino acids, and vitamins, were analyzed, says Ulrich. "This study covered most of the known biochemical pathways in the body."

Ref : http://cebp.aacrjournals.org/content/early/2015/11/17/1055-9965.EPI-15-0697.abstract?sid=c6453fd8-4a41-4a96-93c4-750c662bace3

Identifying new mechanism for aspirin in cancer prevention

Research finding offers hope for more powerful aspirin-like drugs

Researchers have found that salicylic acid targets the activities of HMGB1, an inflammatory protein associated with a wide variety of diseases, offering hope that more powerful aspirin-like drugs may be developed.

Aspirin is one of the oldest and most commonly used medicines, but many of its beneficial health effects have been hard for scientists and physicians to explain. A recent study conducted by researchers at the Boyce Thompson Institute (BTI), in collaboration with colleagues at Rutgers University and San Raffaele University and Research Institute, shows that aspirin's main breakdown product, salicylic acid, blocks HMGB1, which may explain many of the drug's therapeutic properties. The findings appear Sept. 23, 2015 in the journal Molecular Medicine.

"We've identified what we believe is a key target of aspirin's active form in the body, salicylic acid, which is responsible for some of the many therapeutic effects that aspirin has. This protein, HMGB1, is associated with many prevalent, devastating diseases in humans, including rheumatoid arthritis, heart disease, sepsis and inflammation-associated cancers, such as colorectal cancer and mesothelioma," said senior author Daniel Klessig, a professor at BTI and Cornell University.

Aspirin's pain relieving effects have long been attributed to its ability to block the enzymes cyclooxygenase 1 and 2, which produce prostaglandins--hormone-like compounds that cause inflammation and pain--a discovery that netted its discoverer, John Vane, a Nobel prize. However, the body rapidly converts aspirin to salicylic acid, which is a much less effective inhibitor of cyclooxygenase 1 and 2 than aspirin. Nonetheless, it has similar pharmacological effects as aspirin, suggesting that salicylic acid may interact with additional proteins.

"Some scientists have suggested that salicylic acid should be called 'vitamin S', due to its tremendous beneficial effects on human health, and I concur," said lead author Hyong Woo Choi, a research associate at BTI.

In the current study, researchers discovered the interaction between salicylic acid and HMGB1 by screening extracts prepared from human tissue culture cells to find proteins that could bind to salicylic acid. They identified one of these proteins as HMGB1. These screens have also identified a key suspect in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, plus approximately two dozen additional candidates that have yet to be characterized.

To further investigate the interactions between salicylic acid and HMGB1's role in the body, Klessig worked with Marco Bianchi of San Raffaele University and Research Institute, who initially discovered that HMGB1 is a trigger of inflammation. Using assays that measured the effects of salicylic acid on the recruitment and activation of immune cells, they showed that salicylic acid could block both of these functions at concentrations similar to those found in people on low-dose aspirin.

"We've found that HMGB1 is involved in countless situations where the body confronts damage to its own cells, which occur in many disease conditions. In retrospect, it's almost obvious that a very general anti-inflammatory compound blocks a very general inflammation trigger," said Bianchi.

Klessig also teamed up with biophysicist Gaetano Montelione at Rutgers, The State University of New Jersey, to not only confirm that salicylic acid can bind to HMGB1, but also to identify the salicylic acid binding sites.

More at research paper

Research finding offers hope for more powerful aspirin-like drugs

Naproxen and omeprazole combination effective in preventing bladder cancer

The anti-inflammatory class of drugs NSAIDs have shown great promise in preventing cancers including colon, esophagus and skin. However, they can increase the risks of heart attacks, ulcers and rare but potentially life-threatening bleeds.

A new study suggests there may be ways to reduce these dangerous side effects. Collaborators from the University of Michigan, the National Cancer Institute and the University of Alabama looked at naproxen, which is known to have a lower cardiovascular risk than other NSAIDs. Naproxen, like most NSAIDs and aspirin, does increase the risk for gastric ulcers or bleeding. Here, the researchers used the proton pump inhibitor omeprazole, a commonly used acid inhibitor, in combination with naproxen and tested its effects on cancer prevention in a rat model of bladder cancer.

They found that naproxen reduced the incidence of bladder cancer by 75 percent in rats. Omeprazole by itself did not affect the development of cancer but it also did not interfere with the effect of naproxen at preventing tumors. The rats who received naproxen alone or naproxen with omeprazole developed cancer at similarly low rates, while all rats receiving omeprazole alone or no treatment developed bladder cancer.

Clinical data in humans has previously shown combining omeprazole plus naproxen reduced gastric toxicity roughly 70 percent.

The authors also found that intermittent dosing with naproxen (three weeks on the drugs, followed by three weeks off) was highly effective and likely to reduce gastric toxicity. However, it does not have the clear clinical data supporting reduced gastric toxicity associated with naproxen and omeprazole.

"Our study shows that naproxen works just as well with a proton pump inhibitor as without. This provides proof of principle that this could be a valuable cancer prevention strategy and one hopes it can advance quickly to a clinical trial for those at high risk of colon, esophageal, squamous cell skin cancer or potentially other cancers," says lead study author Ronald A. Lubet, Ph.D., a scientist with the Chemopreventive Agent Development Research Group at the National Cancer Institute.

Naproxen and omeprazole combination effective in preventing bladder cancer

Aspirin May Fight Cancer by Slowing DNA Damage

Researchers hypothesized that NSAIDs modulate clonal evolution by reducing SGA acquisition rate. Researchers  evaluated thirteen individuals with BE. Eleven had not used NSAIDs for 6.2±3.5 (mean±standard deviation) years and then began using NSAIDs for 5.6±2.7 years, whereas two had used NSAIDs for 3.3±1.4 years and then discontinued use for 7.9±0.7 years. 161 BE biopsies, collected at 5–8 time points over 6.4–19 years, were analyzed using 1Million-SNP arrays to detect SGAs. Even in the earliest biopsies there were many SGAs (284±246 in 10/13 and 1442±560 in 3/13 individuals) and in most individuals the number of SGAs changed little over time, with both increases and decreases in SGAs detected. The estimated SGA rate was 7.8 per genome per year (95% support interval [SI], 7.1–8.6) off-NSAIDs and 0.6 (95% SI 0.3–1.5) on-NSAIDs. Twelve individuals did not progress to EA. In ten we detected 279±86 SGAs affecting 53±30 Mb of the genome per biopsy per time point and in two researchers detected 1,463±375 SGAs affecting 180±100 Mb. In one individual who progressed to EA we detected a clone having 2,291±78 SGAs affecting 588±18 Mb of the genome at three time points in the last three of 11.4 years of follow-up. NSAIDs were associated with reduced rate of acquisition of SGAs in eleven of thirteen individuals. Barrett's cells maintained relative equilibrium level of SGAs over time with occasional punctuations by expansion of clones having massive amount of SGAs. More...

Aspirin May Fight Cancer by Slowing DNA Damage | ucsf.edu

Beta blocker use linked to NSCLC patient survival

Analysis shows that the 155 NSCLC patients given incidental beta blockers had significant better distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival than the 567 patients who were not given the agents.

However, beta blocker use had no impact on locoregional progression-free survival (LRPFS), leading the researchers to suggest that "the drugs may be affecting the tumor metastatic cascade rather than affecting the primary tumor."

The team investigated the impact of beta blockers on newly diagnosed NSCLC patients at the MD Anderson Cancer Center between 1998 and 2010 following reports that norepinephrine may stimulate tumor cell migration - a process could be targeted via the beta-adrenergic receptor.

Beta blocker use significantly predicted longer DMFS (hazard ratio [HR]=0.67), DFS (HR=0.74), and OS (HR=0.78), after adjusting for confounders including age, cancer stage, histology, tumor volume, Karnofsky performance score, use of concurrent chemotherapy, and radiation dose. Other factors including presence of hypertension or chronic obstructive pulmonary disease, and use of aspirin were also considered in the multivariate analysis.

The researchers note that 68% of patients were given beta blockers for hypertension. The remaining patients were given beta blockers for nonhypertensive disorders such as coronary heart disease.

Most patients were given selective (β1) beta blockers such as metoprolol (n=89)(left structure) and atenolol (above right structure)(n=43). Just 21 of the patients were given nonselective agents, such as carvedilol.

Beta blocker use linked to NSCLC patient survival

Flavonoid Compound Found in Foods and Supplements May Prevent the Formation of Blood Clots, Study Suggests...

A compound called  rutin (see structure - a quercetin derivative), commonly found in fruits and vegetables and sold over the counter a dietary supplement, has been shown to inhibit the formation of blood clots in an animal model of thrombosis.

 As per the researchers claim,

"Approximately half of all morbidity and mortality in the United States can be attributed to heart attack or stroke."..

The study focused on protein disulfide isomerase (PDI) which is found in all cells. Investigators in BIDMC's Division of Hemostasis and Thrombosis had previously shown that PDI is rapidly secreted from both platelets and endothelial cells during thrombosis, when a clot forms in a blood vessel, and that inhibition of PDI could block thrombosis in a mouse model.

"This was a transformative and unanticipated finding because it identified, for the first time, that PDI is secreted from cells in a live animal and is a potential target for preventing thrombosis," says Flaumenhaft. However, because intracellular PDI is necessary for the proper synthesis of proteins, the scientists had to identify a specific compound that could block the thrombosis-causing extracellular PDI -- without inhibiting the intracellular PDI.

They began by conducting a high-throughput screen of a wide array of compounds to identify PDI inhibitors. Among the more than 5,000 compounds that were screened, quercetin-3-rutinoside (rutin) emerged as the most potent agent. "Rutin was essentially the champion compound," says Flaumenhaft.

A bioflavonoid that is naturally found in many fruits, vegetables and teas including onions, apples and citrus fruits, rutin is also sold as an herbal supplement, having received a special designation for safety from the U.S. Food and Drug Administration (FDA). Surprisingly, studies of the rutin molecule demonstrated that the same part of the molecule that provides rutin with its ability to inhibit PDI also prevents the compound from entering cells."That finding explained how this compound can be both a potent inhibitor of PDI and a safe food supplement," says Flaumenhaft. "Our next questions were, 'Is this compound anti-thrombotic? Can it prevent blood clots?'"

Clues to aspirin's anti-cancer effects revealed.....................

In continuation of my update on aspirin....

One of the world's oldest medicines may hold the secret to a very contemporary problem: preventing cancer. Exactly why salicylate shows such potential as an anti-cancer treatment remains unclear, but a new study in mice offers clues.

Salicylate, found in willow bark, has been a key ingredient in medicine cabinets for thousands of years – ancient Egyptian manuscripts describe it as a treatment for inflammation. In a modified form – aspirin – it remains a successful anti-inflammatory and analgesic. Recently, though, research has revealed a puzzling side-effect of taking aspirin: the drug seems to lower a person's chances of developing some forms of cancer.

Aspirin is rapidly broken down inside the body into salicylate, so to investigate aspirin's unexpected side-effects Grahame Hardie at the University of Dundee, UK, applied salicylate to cultured human cells derived from the kidney. He found that the drug activated AMPK, an enzyme involved in cell growth and metabolism that has been found to play a role in cancer and diabetes.

"This is an ancient herbal remedy which has probably always been part of the human diet," says Hardie. "But despite that we're still finding out how it works."

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.

"That's what makes aspirin so scientifically and clinically interesting," says Chris Paraskeva at the University of Bristol, UK, who was not involved in the work. "It potentially works through a number of different pathways."

Ref : http://www.sciencemag.org/content/early/2012/04/18/science.1215327

Experimental Drug-apixaban (Eliquis) : Might Beat Aspirin in Preventing Repeat Strokes: Study

An investigational drug called apixaban (Eliquis) appears to be better than aspirin at preventing blood clots in certain patients who have already suffered a stroke or so-called "mini-stroke" due to an abnormal heart rhythm, according to the results of a new study.

For patients with the dangerous irregular heart rhythm known as atrial fibrillation who can't tolerate the standard drug treatment, daily apixaban seems to be more effective at warding off a stroke or blood clot than aspirin, the study found.

More....

Ginger Supplements Might Ease Inflammation Linked to Colon Cancer..

A small, preliminary study finds that ginger root supplements seem to reduce inflammation in the intestines  a potential sign that the pills might reduce the risk of colon cancer. Previous research in animals has suggested that ginger can reduce inflammation but isn't potentially toxic to the stomach like aspirin, Zick noted. And scientists have linked chronic inflammation in the gut to colon cancer, suggesting that easing this inflammation could reduce the risk of the disease.

In the new study, Zick's team randomly assigned 30 people to take pills containing 2 grams of ground ginger root extract or a "dummy" placebo pill each day for 28 days. They measured the level of inflammation in the participants' intestines before and after the test period. The researchers found that the level of inflammation in the subjects who took the ginger pills fell by an average of 28 percent, while staying about the same in those who took the placebo.

Ref : http://cancerpreventionresearch.aacrjournals.org/content/early/2011/10/07/1940-6207.CAPR-11-0224.abstract

New anti-inflammatory drug shows promise for treating inflammatory disorders

In one of my earlier blog, I  did mention about the antiinflammatory activity of H₂S gas. Now interestingly John Wallace, a pharmacologist and director of the Farncombe Family Digestive Health Research Institute at McMaster University, compared naproxen, a commonly used NSAID, to a novel anti-inflammatory drug, ATB-346 (ATB-346 is a derivative of naproxen which releases hydrogen sulfide), which he developed in collaboration with a team of Italian chemists and is now commercializing through his company, Antibe Therapeutics Inc. The basis for this research is by the fact that hydrogen sulphide is an important mediator of gastric mucosal defence. As we all know the ulcerogenecity associated with NSAIDs, there is a need to have NSAIDs with least or no ulcerogenecity.

As per the claim by the researchers, ATB-346, [above, structure : 2-(6-methoxy-napthalen-2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester] acts by inhibiting cyclooxygenase-1 and 2 and  reduces inflammation (in vivo). More interesting out come from their research is  that ATB-346 suppressed gastric prostaglandin E₂ synthesis as effectively as naproxen, but produced negligible damage in the stomach and intestine. 

ATB-346 did not cause significant damage, where as naproxen rendered significant  gastric mucosa damage (e.g. ablation of sensory afferent nerves, inhibition of endogenous nitric oxide or hydrogen sulphide synthesis, co-administration with aspirin, antagonism of K_IR6.x channels). Unlike naproxen and celecoxib, ATB-346 accelerated healing of pre-existing gastric ulcers. In a mouse airpouch model, ATB-346 suppressed cyclooxygenase-2 activity and inhibited leukocyte infiltration more effectively than naproxen. ATB-346 was as effective as naproxen in adjuvant-induced arthritis in rats, with a more rapid onset of activity, but with substantially reduced gastrointestinal toxicity (100 times safer than naproxen). Unlike naproxen, ATB-346 did not elevate blood pressure in hypertensive rats.

The researchers concluded that H2S-releasing NSAIDs appear to represent a promising alternative to existing therapies for the treatment of inflammation and pain. Future research will focus on the potential cardiovascular benefits of these drugs. .....

Ref : John L Wallace et. al., British Journal of Pharmacology, 159(6),  1236 - 1246

Brilinta (Ticagrelor) better than Plavix. ?.......

W knew that, Astra-Zeneca,  in its PLATO clinical trial in mid-2009,  found that ticagrelor had better mortality rates than clopidogrel (9.8% vs. 11.7%, p<0.001) in treating patients with acute coronary syndrome. Patients given ticagrelor were less likely to die from vascular causes, heart attack, or stroke but had slightly greater chances of major bleeding which was non-significant (11.6 vs. 11.2, p=0.4). Like clopidogrel and ticlopidine, ticagrelor blocks ADP receptors of subtype P2Y₁₂. In contrast to the other antiplatelet drugs, the blockage is reversible. Moreover, it does not need hepatic activation, which could reduce the risk of drug interactions-which makes it special.

Now this has been further substantiated by Dr. Chris. Cannon, who claims that  clot-busting drug Ticagrelor (Brilinta), may soon take the place of Clopidogrel (Plavix) in treating patients with acute coronary syndrome, which includes angina and heart attack.

In a new trial (by Dr. Christopher Cannon, a cardiologist with Brigham and Women's Hospital and an associate professor of medicine at Harvard Medical School, both in Boston), the upstart drug ticagrelor (Brilinta) reduced the risk of second heart attacks and death without raising the risk of bleeding, as clopidogrel (Plavix) can do and the authors claim  that this is pretty compelling evidence from this trial that ticagrelor is better without any increased risk of bleeding. 

In this study (funded by AstraZeneca) of more than 13,000 patients with acute coronary syndrome, Brilinta, appears to be more potent than Plavix and has  emerged with several advantages over the old standby  claims the researchers.

Brilinta is s processed as soon as it's swallowed (meaning it doesn't have to go through the liver), and kicks in faster than Plavix, where as Plavix (usually in combination with aspirin) has its share of problems, namely a lag time between when it is administered and when it takes effect, and variability in how different individuals respond to it. And because of an increased risk of bleeding, Plavix must be discontinued before surgery. Overall the researchers, claim that Brilinta has a more reliable level of anti-clotting effect. There's less variability. At the dose, it has about twice the level of anti-clotting effect and hence the  benefit in preventing heart attacks and stent thrombosis. The authors attribute the reason for the superiority of the drug to its quicker reversblity (than Plavix) and patients could have surgery with a lower risk of bleeding. FDA is expected to approve the drug late this year and  hope the patients with thrombosis, angina and acute coronary syndrome will breathe a sigh of relief...

Ref : http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2809%2962191-7/fulltext

Silver nano particles as antiplatelet agent?

We know common side effects of anti-thrombotic agents [aspirin & Reo Pro (abciximab) ] like dangerous bleeding and ulcerogenecity (of aspirin) so there is an urgent need to have more safer antiplatelet agents. Now thanx to Debabrata Dash and colleagues of Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi for their innovative findings that is., now silver nano particles can be used as antiplatelet agent.

The scientists describe development and lab testing of silver nanoparticles that seem to keep platelets in an inactive state. Low levels of the nanosilver, injected into mice, reduced the ability of platelets to clump together by as much as 40 percent with no apparent harmful side effects. The nanoparticles "hold immense potential to be promoted as an antiplatelet agent," the researchers note. Nanosilver appears to possess dual significant properties critically helpful to the health of mankind — antibacterial and antiplatelet — which together can have unique utilities, for example in coronary stents. One more "Nano" to the drug discovery kitty. Congrats Dash and group for this achievement. More...