Drug trio of rapamycin, sildenafil and doxorubicin improved effectiveness of cancer treatment, protected heart

Combining cancer medication with a drug for erectile dysfunction and one for heart transplants helped kill cancer cells and protected the heart from damage. For decades, doxorubicin has been a powerful anti-cancer treatment for various human cancers, including breast, ovarian, colon and prostate. But its use has been limited due to harmful, possibly irreversible effects on the heart.

In this study, using cell and animal models, researchers found that sildenafil alone or in combination with rapamycin (an immunosuppressant used to prevent post-transplant organ rejection) significantly improved the anti-cancer effects of doxorubicin while protecting the heart. The combination of all three medications showed the most powerful effect, researchers said.

"Because sildenafil and rapamycin are clinically approved drugs that both protect heart muscle, we thought that combining these drugs with doxorubicin would be a unique strategy to eliminate the cardiac side effects of doxorubicin while further improving its cancer-killing ability," said Rakesh Kukreja, Ph.D., study co-author and professor of internal medicine and cardiology, Virginia Commonwealth University (VCU) School of Medicine in Richmond.

"The drug combination led to a dramatic protection of heart muscle from apoptosis (cellular self-destruction) and, to a lesser extent, necrosis (cell death from disease)," said David E. Durrant, study lead author and Ph.D. candidate at the VCU School of Medicine. "We think this combination therapy may have excellent potential to move forward into clinical trials and eventually improve life expectancy of cancer patients."

Drug trio improved effectiveness of cancer treatment, protected heart

Breast cancer drug, geldanamycin could halt other tumors

The drug, geldanamycin, is well known for attacking a protein associated with the spread of breast cancer. However, a laboratory-based study found it also degraded a different protein that triggers blood vessel growth.

Ref : http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0048539

Breast cancer drug Geldanamycin, could halt other tumors

New targeted therapy for advanced prostate cancer shows anti-tumour activity in phase I clinical trials

Researchers lead by Prof. Daniel Petrylakwill reports that,  a new drug that specifically targets a protein found on the surface of prostate cancer cells has performed well in a phase I clinical trial, and a phase II trial has started. The drug reduced levels of circulating tumour cells (CTC) and levels of prostate specific antigen (PSA), a marker for tumour activity, in patients who had already failed previous chemotherapy and hormone treatments.

The drug is made up of a monoclonal antibody, which targets a protein called prostate specific membrane antigen (PSMA), linked to a cancer cell-killing drug called monomethyl auristatin E (MMAE see structure), which disrupts tubulins, the tiny molecules inside a cell that are essential for cell division. The PSMA antibody drug conjugate (PSMA ADC) binds to the PSMA on the surface of the prostate cancer cell and is absorbed into the cell where the MMAE is released, causing cell cycle arrest and cell death.

Prof.Daniel Petrylak, who was Professor of Medicine at Columbia University Medical Center (USA) when the phase I trial started and who is now Director of the Prostate Cancer Program/Genitourinary Cancer Program and co-director of the Signal Transduction Program at Yale University Medical Centre (USA), said: "By conjugating the antibody with a chemotherapeutic agent, we hoped that this would lead to more targeted therapy, which would have fewer toxic side-effects and would be more effective against the cancer."

Prof Petrylak and his colleagues from other US cancer centres recruited 50 patients to the phase I clinical trial. The patients had the most advanced form of prostate cancer, which had spread to the bone and other organs; they had failed hormone therapy and had received up to two previous chemotherapies. The researchers treated them with doses of PSMA ADC at levels ranging from 0.4 to 2.8 mg/kg, by intravenous infusion, over a period of three weeks per cycle, and for up to four treatment cycles.

The researchers detected antitumour activity among the patients who were treated at the higher doses. About half of the patients who received doses of 1.8 mg/kg or more showed either a 50% or more reduction in PSA levels, or a fall in CTC in the blood to less than five cells per 7.5 ml of blood, or both.

The drug was generally well tolerated by patients, although levels of white blood cells were significantly reduced (neutropenia) at the highest dose of 2.8 mg/kg and one patient died. The researchers say the cause of the death is unclear.

Prof Petrylak said: "These results show that PSMA ADC has anti-tumour activity in patients who have failed up to two prior chemotherapies and hormone therapy. We have initiated a phase II trial of up to 75 patients in which the recommended dose will be 2.5 mg/kg. This new trial will evaluate responses in PSA and CTC; it will evaluate control of metastases in bone, internal organs and lymph nodes; and it will look at the effect on pain. Safety also will be assessed.

"The fact that this new targeted therapy is active against the most advanced forms of prostate cancer is encouraging, as few or no therapeutic options are available at present."

 More...

New targeted therapy for advanced prostate cancer shows anti-tumour activity in phase I clinical trials

Cinacalcet failure raises trial conduct issues.....

We know that, Cinacalcet (see above structure) is a drug that acts as a calcimimetic (i.e. it mimics the action of calcium on tissues) by allosteric activation of the calcium-sensing receptor that is expressed in various human organ tissues. It is sold by Amgen under the trade name Sensipar in North America and Australia and as Mimpara in Europe. Cinacalcet is used to treat secondary hyperparathyroidism (elevated parathyroid hormone levels), a consequence of having end-stage renal disease.   Cinacalcet is also indicated for the treatment of hypercalcemia in patients with parathyroid carcinoma. 

http://www.news-medical.net/news/20121116/Cinacalcet-failure-raises-trial-conduct-issues.aspx  

Drinking green tea with starchy food may help lower blood sugar spikes

In continuation on my update on green tea

Mice fed an antioxidant found in green tea  epigallocatechin-3-gallate, or EGCG  and corn starch had a significant reduction in increase in their blood sugar  blood glucose  levels compared to mice that were not fed the compound, according to Joshua Lambert, assistant professor of food science in agricultural sciences.

The dose of EGCG fed to the mice was equivalent to about one and a half cups of green tea for a human. Lambert, who worked with Sarah C. Forester, postdoctoral fellow, and Yeyi Gu, graduate student, both in food science, said EGCG was most effective when the compound was fed to the mice simultaneously with corn starch. For humans, this may mean that green tea could help them control the typical blood sugar increases that are brought on when they eat starchy foods, like breads and bagels that are often a part of typical breakfasts.

"The spike in blood glucose level is about 50 percent lower than the increase in the blood glucose level of mice that were not fed EGCG," Lambert said. 

Metformin more effective than sulfonylurea in controlling type 2 diabetes

In continuation of my update on Metformin

A Vanderbilt study examining the impact of the two most commonly prescribed oraldiabetes medications on the risk for heart attack, stroke and death has found the drug metformin has benefits over sulfonylurea drugs.

It was important to examine the cardiovascular impact of the more commonly used diabetes drugs after recent controversy surrounded another diabetes medication, rosiglitazone, because it was associated with an increased cardiac risk, said lead author, Christianne L. Roumie, M.D., MPH, assistant professor of Internal Medicine and Pediatrics. Smaller studies pointed to a potential advantage of taking the drug metformin but this study confirms this in a large population.

"We demonstrated that for every 1,000 patients who are using metformin for a year there are two fewer heart attacks, strokes or deaths compared with patients who use sulfonylureas. I think this reinforces the recommendation that metformin should be used as the first medication to treat diabetes," Roumie said.

The researchers looked at the charts of more than 250,000 veterans receiving care in Veterans Health Administration hospitals throughout the United States.

More...

Metformin more effective than sulfonylurea in controlling type 2 diabetes

Scientists show how sorafenib can be dangerous to the heart..

In continuation of my update on sorafenib

Studying mice with the equivalent of a heart attack, researchers found that the drug sorafenib (Nexavar) - which inhibits proteins called tyrosine kinase receptors (RTKs), and is used in kidney and liver cancer treatment - can interfere with heart stem cell activity, affecting the heart's ability to repair itself after injury. The findings suggest that sorafenib and other similar drugs that target these kinds of protein receptors may raise the risk for heart attack for some cancer patients with underlying heart disease, as well as affect the heart's ability to repair damage. By understanding how these cancer drugs can affect the heart, scientists and clinicians may be able to devise new treatment strategies to lessen such potentially damaging effects of often vital cancer drugs.

"The goal is not to take the drug off of the market - it's a very good and useful drug that cancer patients need. We're trying to understand how this cancer drug and others like it can affect the heart, and what types of individuals might be at risk for problems," said senior author Steven Houser, PhD, Professor and Chair of Physiology at Temple University School of Medicine and Director of Temple's Cardiovascular Research Center. "Our results are beginning to provide a clearer picture of some of the potential physiological mechanisms at play."

Ref : http://heartsurgery.templehealth.org/content/news.htm?inCtx4news_id=42&inCtx4view=24

Scientists show how sorafenib can be dangerous to the heart

Compound in grapes Resveratrol, red wine could be key to fighting prostate cancer

In continuation of my update on Resveratrol

We know that, Resveratrol, a compound found commonly in grape skins and red wine, has been shown to have several beneficial effects on human health, including cardiovascular health and stroke prevention. Now, a University of Missouri researcher has discovered that the compound can make prostate tumor cells more susceptible to radiation treatment, increasing the chances of a full recovery from all types of prostate cancer, including aggressive tumors.

Ref : http://www.andrologyjournal.org/cgi/content/abstract/33/4/752

http://onlinelibrary.wiley.com/doi/10.1111/j.1349-7006.2012.02272.x/abstract;jsessionid=2638CB82B18F3EF652F3261E74A75CCA.d01t02

Compound in grapes, red wine could be key to fighting prostate cancer

Biologists determine how blind mole rats fight off cancer

In continuation of my update on mole rats..

Biologists at the University of Rochester have determined how blind mole rats fight off cancer-and the mechanism differs from what they discovered three years ago in another long-lived and cancer-resistant mole rat species, the naked mole rat.

The team of researchers, led by Professor Vera Gorbunova and Assistant Professor Andrei Seluanov, found that abnormally growing cells in blind mole rats secrete the interferon beta protein, which causes those cells to rapidly die. Seluanov and Gorbunova hope the discovery will eventually help lead to new cancer therapies in humans. Their findings are being published this week in the Proceedings of the National Academy of Sciences.

Blind mole rats and naked mole rats-both subterranean rodents with long life spans-are the only mammals never known to develop cancer. Three years ago, Seluanov and Gorbunova determined the anti-cancer mechanism in the naked mole rat. Their research found that a specific gene-p16-makes the cancerous cells in naked mole rats hypersensitive to overcrowding, and stops them from proliferating when too many crowd together.

"We expected blind mole rats to have a similar mechanism for stopping the spread of cancerous cells," said Seluanov. "Instead, we discovered they've evolved their own mechanism."

Biologists determine how blind mole rats fight off cancer

New medication lomitapide, shows promise as lipid-lowering therapy for rare cholesterol disorder

Penn researchers have found that,   lomitapide (see structure)  a first-in-class microsomal triglyceride transfer protein (MTP) inhibitor, substantially and stably reduced LDL cholesterol (the "bad" cholesterol) in patients with the orphan disease homozygous familial hypercholesterolemia (HoFH). Lomitapide works by inhibiting MTP, which is required for the production of VLDL,  the precursor to LDL.

The current study was an open-label trial that comprised a six-month phase designed to assess the efficacy of lomitapide when added to standard of care and an additional year-long phase to assess safety and tolerability. Twenty-nine adult HoFH patients from across the world were enrolled, with 23 patients completing both the efficacy and the safety phases. All of the patients received lomitapide along with conventional lipid-lowering therapies including statins and, in some cases, apheresis. The lomitapide dose was gradually increased from 5 mg to a maximum tolerated dose of up to 60 mg per day. Median dose was 40 mg per day. At the end of the efficacy phase, LDL-C levels were reduced by an average of 50 percent from baseline. Approximately one-third of the patients experienced levels of LDL-C that were less than 100 mg/dl -- close to the recommended therapeutic goals -- at some point during the study, and concomitant lipid-lowering therapy was modified in a subset of these patients during the safety phase. Despite these changes in treatment, patients' mean LDL-C levels were still reduced by 38 percent at the end of the study.

"The magnitude of this reduction in LDL-C and the fact that some patients reached or approached the LDL-C therapeutic goals is truly remarkable for this high risk population that historically doesn't respond to lipid-lowering drugs," said the study's lead author, Marina Cuchel, MD, PhD, research assistant professor of Medicine at Penn. "A reduction in LDL-C of this magnitude is certainly expected to favorably alter the clinical course of this devastating disease."

Ref : http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61731-0/fulltext

New medication shows promise as lipid-lowering therapy for rare cholesterol disorder

DHA supplementation enhances high-frequency, stimulation-induced synaptic transmission in mouse hippocampus - Applied Physiology, Nutrition, and Metabolism

In continuation of my update on DHA...

A team led by Yves Sauve, who is a member of the University of Alberta's Faculty of Medicine & Dentistry, divided ten mice to receive a diet supplemented with DHA or an unsupplemented diet.  Animals that received DHA-enhanced diets were found to have a 29 percent higher level of DHA in the brain's hippocampus region—which is involved in memory--compared to the control group.  Higher DHA levels were associated with increased synaptic transmission in the hippocampus following brief stimulation.  “This increase in synaptic transmission might provide a physiological correlation for the improved spatial learning and memory observed following DHA supplementation,” the authors conclude.

"We wanted to find out how fish intake improves memory," explained Dr Sauve, who works in the University's department of physiology, the department of ophthalmology and the Centre for Neuroscience. "What we discovered is that memory cells in the hippocampus could communicate better with each other and better relay messages when DHA levels in that region of the brain were higher. This could explain why memory improves on a high-DHA diet."

He added that supplementing your diet with DHA, either by increasing fish intake or by consuming omega-3 supplements, may help protect against reduced brain DHA levels as we age. 

Ref : http://www.nrcresearchpress.com/doi/abs/10.1139/h2012-062#.UJSh1sH3Th8

DHA supplementation enhances high-frequency, stimulation-induced synaptic transmission in mouse hippocampus - Applied Physiology, Nutrition, and Metabolism

Omega-3 supplementation improves working memory in young adults

In continuation of my update on omega fatty acid

University of Pittsburgh researchers led by Rajesh Narendran of the Department of Radiology tested the effects of a supplement providing 930 milligrams eicosapentaenoic acid (EPA) and 750 milligrams docosahexaenoic acid (DHA) in 11 men and women between the ages of 18 and 25. Evaluation of working memory (via an "n-back test"), positron emission tomography (PET) imaging of the brain and tests for red blood cell fatty acid levels were conducted before and after the six month treatment period.

Participants experienced an increase in plasma omega-3 fatty acid levels and improvement in working memory at the end of six months. "What was particularly interesting about the presupplementation n-back test was that it correlated positively with plasma omega-3,"observed Bita Moghaddam, whose lab conducted the research. "This means that the omega-3s they were getting from their diet already positively correlated with their working memory."

"Before seeing this data, I would have said it was impossible to move young healthy individuals above their cognitive best," he remarked. "We found that members of this population can enhance their working memory performance even further, despite their already being at the top of their cognitive game."

Although the researchers had suggested increases in dopamine storage and a protein involved in decision making in a particular area of the brain as mechanisms supporting omega-3's effect on cognitive function, PET scan results failed to support the hypothesis. "It is really interesting that diets enriched with omega-3 fatty acid can enhance cognition in highly functional young individuals," Dr Narendran commented. "Nevertheless, it was a bit disappointing that our imaging studies were unable to clarify the mechanisms by which it enhances working memory."

Green tea found to reduce rate of some GI cancers

In continuation of my update on green tea.

We know that, Tea contains polyphenols or natural chemicals that include catechins like EGCG and ECG. Catechins have antioxidant properties and may inhibit cancer by reducing DNA damage and blocking tumor cell growth and invasion.

Now researchers have found that regular tea consumption, defined as  tea  consumption  at  least three times a week for more than six months, was  associated  with  a  17 percent reduced risk of all digestive cancers combined. A  further  reduction  in  risk  was  found to be  associated  with  a increased level of tea drinking. Specifically, those who consumed about two to three cups per day (at least 150 grams of tea per month) had a 21 percent reduced risk of digestive system cancers.

For all digestive system cancers combined, the risk was reduced by 27 percent among women who had been drinking tea regularly for at least 20 years," said Nechuta. "For colorectal cancer, risk was reduced by 29 percent among the long-term tea drinkers. These results suggest long-term cumulative exposure may be particularly important."

Ref : http://ajcn.nutrition.org/content/96/5/1056

Green tea found to reduce rate of some GI cancers

Caffeine's effect on the brain's adenosine receptors visualized for the first time

In continuation on my update on coffee

Molecular imaging with positron emission tomography (PET) has enabled scientists for the first time to visualize binding sites of caffeine in the living human brain to explore possible positive and negative effects of caffeine consumption. According to research published in the November issue of The Journal of Nuclear Medicine, PET imaging with F-18-8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (F-18-CPFPX) shows that repeated intake of caffeinated beverages throughout a day results in up to 50 percent occupancy of the brain's A₁adenosine receptors.

"There is substantial evidence that caffeine is protective against neurodegenerative diseases like Parkinson's or Alzheimer's disease," noted Elmenhorst. "Several investigations show that moderate coffee consumption of 3 to 5 cups per day at mid-life is linked to a reduced risk of dementia in late life. The present study provides evidence that typical caffeine doses result in a high A₁ adenosine receptor occupancy and supports the view that the A₁ adenosine receptor deserves broader attention in the context of neurodegenerative disorders." 

Caffeine's effect on the brain's adenosine receptors visualized for the first time

New target discovered for food allergy treatment

New target discovered for food allergy treatment: Researchers have discovered a novel target for the treatment of food allergies. Levels of the enzyme Pim 1 kinase rise in the small intestines of peanut-allergic mice. Inhibiting activity of Pim 1 markedly reduced the allergic response to peanuts.