Rapamycin lotion reduces facial tumors caused by tuberous sclerosis, team reports

In continuation of my update on rapamycin 

Addressing a critical issue for people with a genetic disorder called tuberous sclerosis complex (TSC), doctors at The University of Texas Health Science Center at Houston (UTHealth) reported that a skin cream containing rapamycin significantly reduced the disfiguring facial tumors affecting more than 90 percent of people with the condition.

Findings of the multicenter, international study involving 179 people with tuberous sclerosis complex appear in the journal JAMA Dermatology.

"People with tuberous sclerosis complex want to look like everyone else," said Mary Kay Koenig, M.D., the study's lead author, co-director of the Tuberous Sclerosis Center of Excellence and holder of the Endowed Chair of Mitochondrial Medicine at McGovern Medical School at UTHealth. "And, they can with this treatment."

Tuberous sclerosis complex affects about 50,000 people in the United States and is characterized by the uncontrolled growth of non-cancerous tumors throughout the body.

While benign tumors in the kidney, brain and other organs pose the greater health risk, the tumors on the face produce a greater impact on a patient's daily life by making them look different from everyone else, Koenig said.

Koenig's team tested two compositions of facial cream containing rapamycin and a third with no rapamycin. Patients applied the cream at bedtime for six months.

"Eighty percent of patients getting the study drug experienced a significant improvement compared to 25 percent of those getting the mixture with no rapamycin," she said.

"Angiofibromas on the face can be disfiguring, they can bleed and they can negatively impact quality of life for individuals with TSC," said Kari Luther Rosbeck, president and CEO of the Tuberous Sclerosis Alliance.

"Previous treatments, including laser surgery, have painful after effects. This pivotal study and publication are a huge step toward understanding the effectiveness of topical rapamycin as a treatment option. Further, it is funded by the TSC Research Program at the Department of Defense. We are so proud of this research," Rosbeck said.

Rapamycin is typically given to patients undergoing an organ transplant. When administered by mouth, rapamycin suppresses the immune system to make sure the organ is not rejected.

Rapamycin and tuberous sclerosis complex are linked by a protein called mTOR. When it malfunctions, tuberous sclerosis complex occurs. Rapamycin corrects this malfunction.

Rapamycin was initially used successfully to treat brain tumors caused by tuberous sclerosis complex, so researchers decided to try it on TSC-related facial tumors. Building on a 2010 pilot study on the use of rapamycin to treat TSC-related facial tumors, this study confirmed that a cream containing rapamycin shrinks these tumors.

As the drug's toxicity is a concern when taken by mouth, researchers were careful to check for problems tied to its use on the skin. "It looks like the medication stays on the surface of the skin. We didn't see any appreciable levels in the bloodstreams of those participating in the study," Koenig said.

The Topical Rapamycin to Erase Angiofibromas in TSC—Multicenter Evaluation of Novel Therapy or TREATMENT trial involved 10 test sites including one in Australia. Koenig said additional studies are needed to gauge the long-term impact of the drug, the optimal dosage and whether the facial cream should be a combined with an oral treatment.

Research explains action of drug that may slow aging, related disease

Rapamycin, an antibiotic and immunosuppressant approved for use about 15 years ago, has drawn extensive interest for its apparent ability at least in laboratory animal tests -- to emulate the ability of dietary restriction in helping animals to live both longer and healthier.

However, this medication has some drawbacks, including an increase in insulin resistance that could set the stage for diabetes. The new findings, published in the Journals of Gerontology: Biological Sciences, help to explain why that happens, and what could be done to address it. They suggest that a combination of rapamycin and another drug to offset that increase in insulin resistance might provide the benefits of this medication without the unwanted side effect.

"This could be an important advance if it helps us find a way to gain the apparent benefits of rapamycin without increasing insulin resistance," said Viviana Perez, an assistant professor in the Department of Biochemistry and Biophysics in the OSU College of Science.

"It could provide a way not only to increase lifespan but to address some age-related diseases and improve general health," Perez said. "We might find a way for people not only to live longer, but to live better and with a higher quality of life."

Age-related diseases include many of the degenerative diseases that affect billions of people around the world and are among the leading causes of death: cardiovascular disease, diabetes, Alzheimer's disease and cancer. Laboratory mice that have received rapamycin have reduced the age-dependent decline in spontaneous activity, demonstrated more fitness, improved cognition and cardiovascular health, had less cancer and lived substantially longer than mice fed a normal diet.

Rapamycin, first discovered from the soils of Easter Island, or Rapa Nui in the South Pacific Ocean, is primarily used as an immunosuppressant to prevent rejection of organs and tissues. In recent years it was also observed that it can function as a metabolic "signaler" that inhibits a biological pathway found in almost all higher life forms --     the  ability to  sense when  food  has
been eaten, energy is available and it's okay for cell proliferation, protein synthesis and growth to proceed.

Called mTOR in mammals, for the term "mammalian target of rapamycin," this pathway has a critical evolutionary value -- it helps an organism avoid too much cellular expansion and growth when energy supplies are insufficient. That helps explain why some form of the pathway has been conserved across such a multitude of species, from yeast to fish to humans.

"Dietary restriction is one of the few interventions that inhibits this mTOR pathway," Perez said. "And a restricted diet in laboratory animals has been shown to increase their lifespan about 25-30 percent. Human groups who eat fewer calories, such as some Asian cultures, also live longer."
Aside from a food intake in laboratory mice that's about 40 percent fewer calories than normal, however, it's been found that another way to activate this pathway is with rapamycin, which appears to have a significant impact even when used late in life. Some human clinical trials are already underway exploring this potential.

A big drawback to long-term use of rapamycin, however, is the increase in insulin resistance, observed in both humans and laboratory animals. The new research identified why that is happening. It found that both dietary restriction and rapamycin inhibited lipid synthesis, but only dietary restriction increased the oxidation of those lipids in order to produce energy.

Rapamycin, by contrast, allowed a buildup of fatty acids and eventually an increase in insulin resistance, which in humans can lead to diabetes. However, the drug metformin can address that concern, and is already given to some diabetic patients to increase lipid oxidation. In lab tests, the combined use of rapamycin and metformin prevented the unwanted side effect.

"If proven true, then combined use of metformin and rapamycin for treating aging and age-associated diseases in humans may be possible," the researchers wrote in their conclusion.

This work was supported by the National Institutes of Health. Collaborators included researchers from Oklahoma University Health Science Center, the Oklahoma City VA Medical Center, University of Michigan-Flint, and South Texas Veterans Health Care System.

"There's still substantial work to do, and it may not be realistic to expect with humans what we have been able to accomplish with laboratory animals," Perez said. "People don't live in a cage and eat only the exact diet they are given. 

Nonetheless, the potential of this work is exciting."

Research explains action of drug that may slow aging, related disease  

Topical Rapamycin Effective for TSC-Related Facial Angiofibromas

In continuation of my  update on Rapamycin

Topical rapamycin seems effective for tuberous sclerosis complex (TSC)-related facial angiofibromas, according to a study published online May 23 in JAMA Dermatology.

Mary Kay Koenig, M.D., from The University of Texas Health Science Center at Houston, and colleagues examined the efficacy and safety of topical rapamycin for TSC-related facial angiofibromas in a study involving 179 patients. Participants were randomized in a 1:1:1 ratio to topical formulation containing 1 percent rapamycin, 0.1 percent rapamycin, or vehicle alone (59, 63, and 57 patients, respectively). The formulation was applied daily to designated areas at bedtime.

The researchers observed clinically meaningful and statistically significant improvement in facial angiofibromas for 1 and 0.1 percent rapamycin versus vehicle only, and for 1 versus 0.1 percent rapamycin; most of the improvement was seen in the first month. The Angiofibroma Grading Scale mean improvement at six months was 16.7, 11.0, and 2.1 points for 1 and 0.1 percent rapamycin and vehicle only, respectively (P < 0.001 for 1 and 0.1 percent versus vehicle only). End-of-treatment photos were rated better than baseline for 81.8, 65.5, and 25.5 percent of patients in the 1 and 0.1 percent rapamycin groups and the vehicle group, respectively (P < 0.001 for all three pairwise comparisons).

"Topical rapamycin appears effective and safe for treatment of TSC-related facial angiofibromas," the authors write. "In this trial, the preferred dose was 1 percent once daily."

Several authors disclosed financial ties to Novartis; one author disclosed ties to MedStudy. Several authors have a provisional patent pending

Ref : https://jamanetwork.com/journals/jamadermatology/article-abstract/2682034?resultClick=1

Rapamycin drug could target neural damage linked to Leigh syndrome

In continuation of my update on rapamycin

Salk Institute scientists showed how an FDA-approved drug boosts the health of brain cells by limiting their energy use. Like removing unnecessary lighting from a financially strapped household to save on electricity bills, the drug--called rapamycin--prolongs the survival of diseased neurons by forcing them to reduce protein production to conserve cellular energy.

Rapamycin has been shown to extend lifespan and reduce symptoms in a broad range of diseases and, at the cellular level, is known to slow down the rate at which proteins are made. But the new Salk research, published in the journal eLife, suggests that rapamycin could also target the neural damage associated with Leigh syndrome, a rare genetic disease, and potentially other forms of neurodegeneration as well.

"Our study shows that protein production in neurons is one of the major utilizers of energy and that neurons of Leigh syndrome degenerate because they can't sustain a high enough level of energy," says Tony Hunter, the Renato Dulbecco Chair and American Cancer Society Professor in Salk's Molecular and Cell Biology Laboratory, who led the research.

Previous studies on rapamycin, which blocks a key energy sensor in cells, found that it can alter the immune system, extend lifespan and treat disorders, including lupus and Alzheimer's disease. Researchers assumed that the drug prevented the neurodegeneration seen in Alzheimer's by encouraging cells to degrade damaged components and aggregated proteins. But recent data hinted that the drug might also have an effect on the mitochondria, organelles that act as cells' powerhouses, producing energy in the form of adenosine triphosphate (ATP).

Xinde Zheng, a research associate in the Hunter lab, was already studying the properties of cells affected by Leigh syndrome, whose inherited neurodegeneration is caused by a mutation in mitochondrial DNA that reduces ATP production. Zheng wondered how rapamycin would affect the neurons plagued by the diseased mitochondria. He and Hunter teamed up with the lab of Rusty Gage, a professor in Salk's Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease. Zheng, together with Leah Boyer, then a researcher in Gage's lab and now director of Salk's Stem Cell Core, generated diseased neurons by taking skin cells from patients with Leigh syndrome, reprogramming them into stem cells in culture and then coaxing them to develop into brain cells in a dish.

Though cells must make proteins to survive, protein production is a highly energy-consuming process and, for diseased cells, the process leaves too few energy reserves to deal with cellular stress or other demands.

"Reducing protein production in aging neurons allows more energy for the cell to put toward folding proteins correctly and handling stress," says Zheng, the first author of the new paper. "The impact of our finding is that modulation of protein synthesis could be a general approach to treating neurodegeneration."

In their study, the team found that Leigh Syndrome neurons decayed in the dish and showed clear signs of energy depletion. Meanwhile, Leigh syndrome neurons exposed to rapamycin had more ATP and showed less degeneration. By turning down the dial on protein production, the diseased and damaged neurons were able to survive longer.

"We are surprised and delighted that rapamycin's effect to reduce protein synthesis as an energy-austerity approach may lead to a potential treatment for mitochondria-related neurodegenerative diseases," says Gage.

This is a good example of the value of studying a disease in a dish, according to Hunter. "It's led to a lot of new insights into the underlying biology of this rare and understudied condition," he adds.

More work is needed to determine whether the findings on rapamycin hold true in animal models of Leigh syndrome and other neurodegenerative diseases, and to ascertain how exactly rapamycin is altering the metabolism of the cells.

Rapamycin drug could target neural damage linked to Leigh syndrome

Transplant drug rapamycin may reduce nerve damage, neuropathic pain after spinal cord injury

In continuation of my update on rapamycin

New research in mice indicates that a drug commonly used to suppress the immune system in recipients of organ transplants may also reduce tissue damage and neuropathic pain after spinal cord injury. The findings are published in the Journal of Orthopaedic Research.

   rapamycin

Rapamycin, which is an inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway, has a variety of cellular functions and is known to possess both immunosuppressant and anti-tumor properties. In their previous work, investigators at the Tohoku University Graduate School of Medicine in Japan found that rapamycin treatment can reduce nerve damage and locomotor impairment after spinal cord injury. In this latest study, the team examined whether rapamycin also reduces neuropathic pain, a state of chronic pain resulting from injury to the nervous system.

Using a mouse model of thoracic spinal cord contusion injury, the researchers divided the mice into rapamycin-treated and control groups. Rapamycin treatment four hours after spinal cord injury significantly improved locomotor function and reduced mechanical and thermal hypersensitivity in the hindpaws. Close examination of the mechanisms involved revealed that treatment decreased the activity of various pathways involved in pain.

If the findings hold true in humans, rapamycin could provide considerable benefits to spinal cord injury patients, up to 80 percent of whom experience clinically significant pain that is described as burning, stabbing, and electric shock-like. "Further studies to clarify the impact and full effects of mTOR signaling are needed in order to support the clinical use of mTOR inhibitors in patients with spinal cord injury," the authors wrote.

Rapamycin effective in mouse model of inherited heart disease and muscular dystrophies

In continuation of my update on Rapamycin (Sirolimus)...

Rapamycin, an immunosuppressant drug used in a variety of disease indications and under study in aging research labs around the world, improved function and extended survival in mice suffering from a genetic mutation which leads to dilated cardiomyopathy (DCM) and rare muscular dystrophies in humans. There are currently no effective treatments for the diseases, which include Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy. The familial form of DCM often leads to sudden heart failure and death when those affected reach their 40s and 50s.

Scientists from the Buck Institute and other organizations focused on mutations in the gene LMNA, which produces A-type lamins. Mutations in this gene are associated with at least 13 diseases, with DCM among the most common. DCM accounts for 60 percent of all cardiomyopathy cases. LMNA mutations may account for up to one-third of patients that are diagnosed as having DCM and conduction disease. DCM causes a thinning of the left ventricle and loss of cardiac function. The study showed that deletion of the LMNA gene led to ramped up activity in the molecular pathway mTOR (mammalian target of rapamycin) and that treatment with rapamycin turns down the abnormal signaling. Senior author Brian K. Kennedy, PhD, President and CEO of the Buck Institute for Research on Aging, says treatment with rapamycin extended mouse lifespan by 60 percent in a relatively rapid onset model of disease.

Ref : http://stm.sciencemag.org/content/4/144/144ra103

Rapamycin effective in mouse model of inherited heart disease and muscular dystrophies

Rapamycin: Limited anti-aging effects

In continuation of my update on Rapamycin

The drug rapamycin is known to increase lifespan in mice. Whether rapamycin slows down aging, however, remains unclear. A team of researchers from the German Center for Neurodegenerative Diseases (DZNE) and the Helmholtz Zentrum München has now found that rapamycin extends lifespan -- but its impact on aging itself is limited. The life-extending effect seems to be related to rapamycin's suppression of tumors, which represent the main causes of death in these mouse strains....

Ref : http://www.jci.org/articles/view/67674

Rapamycin: Limited anti-aging effects

Rapamycin as a potential treatment for kidney disease (ADPKD).........

I did  mention about the use of Rapamycin (see structure)  to improve the  efficacy of tuberculosis vaccine in my earlier blog. This drug has been already  used as an immunosuppressant drug to prevent rejection in organ transplantation,  especially useful in kidney transplants.

 Rapamycin, was originally developed as an antifungal agent. However, this was abandoned when it was discovered that it had potent immunosuppressive and antiproliferative properties. Some researchers have  also reported that  the drug prolong the life of mice and might also be useful in the treatment of certain cancers.

Researchers from UC Santa Barbara  earlier claimed that, rapamycin has  a potential to treat  kidney disease,  however  concluded  that the  mice had different genes affected than human patients. Interestingly, the same researchers recently found that  "rapamycin is also highly effective in a new mouse model in which the same gene is affected as in most human patients".

As claimed by the lead researcher, Thomas Weimbs currently, no treatment exists to prevent or slow cyst formation and most ADPKD patients require kidney transplants or lifelong dialysis for survival. I think this will boost the confidence of the several international groups,  who are undertaking the  clinical trials  to test the safety and efficacy of rapamycin and related drugs in polycystic kidney disease. Though the  researchers are hopeful of positive results  they caution that,  it will be critical to balance any benefits against the expected side effects to judge whether these drugs should be recommended for the treatment of polycystic kidney disease. Let us be optimistic.....

Ref : http://www.ia.ucsb.edu/pa/display.aspx?pkey=2164

Combination of metformin and rapamycin shows potential in treating aging and related diseases

A proven approach to slow the aging process is dietary restriction, but new research in the Linus Pauling Institute at Oregon State University helps explain the action of a drug that appears to mimic that process - rapamycin.

Rapamycin, an antibiotic and immunosuppressant approved for use about 15 years ago, has drawn extensive interest for its apparent ability - at least in laboratory animal tests - to emulate the ability of dietary restriction in helping animals to live both longer and healthier.

However, this medication has some drawbacks, including an increase in insulin resistance that could set the stage for diabetes. The new findings, published in the Journals of Gerontology: Biological Sciences, help to explain why that happens, and what could be done to address it.

They suggest that a combination of rapamycin and another drug to offset that increase in insulin resistance might provide the benefits of this medication without the unwanted side effect.

"This could be an important advance if it helps us find a way to gain the apparent benefits of rapamycin without increasing insulin resistance," said Viviana Perez, an assistant professor in the Department of Biochemistry and Biophysics in the OSU College of Science.

"It could provide a way not only to increase lifespan but to address some age-related diseases and improve general health," Perez said. "We might find a way for people not only to live longer, but to live better and with a higher quality of life."

Age-related diseases include many of the degenerative diseases that affect billions of people around the world and are among the leading causes of death: cardiovascular disease, diabetes, Alzheimer's disease and cancer.

Combination of metformin and rapamycin shows potential in treating aging and related diseases

Compounds outsmart solid tumors' malfunctioning machinery

In continuation of my update on Rapamycin

"Allosteric regulators are better than proteasome-affecting agents used in clinics because they do not induce classical drug resistance," Dr. Gaczynska said. "They bind to sites on the proteasome molecule used by natural regulatory proteins. They are more specific and are not restricted to proteasome inhibition but can activate the proteasome under certain conditions."

The new strategy was serendipitously found during experiments with rapamycin, a drug that in a highly publicized study by the UT Health Science Center's Barshop Institute for Longevity and Aging Studies was found to extend life span in mice.

Potential

The Molecular Pharmacology report and follow-up studies describe the unexpected and highly desired effects that rapamycin and similar compounds elicit on the proteasome. Based on these studies, it would be possible to design a new line of proteasome regulators with anti-cancer properties, Drs. Osmulski and Gaczynska said.... 

Ref : http://molpharm.aspetjournals.org/content/84/1/104

Compounds outsmart solid tumors' malfunctioning machinery

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

Combination of Two Drugs Reverses Liver Tumors.....

The combination of two inhibitors of protein mTOR stops the growth of primary liver cancer and destroys tumour cells, according to a study by researchers of the Group of Metabolism and Cancer at Bellvitge Biomedical Research Institute (IDIBELL).  

The study led by IDIBELL researchers compared the effects in mice of two inhibitors of mTOR. The first was a derivative of rapamycin, called everolimus (RAD001 - see structure below left),
which is already used as an immunosuppressant and to treat specific cancers. The second is a new generation drug that inhibits mTOR called BEZ235 (see right side structure). 

During the study, researchers found unexpectedly that the combination of the two drugs had a more potent effect than any of the two drugs separately. Coadministration of BEZ235 and RAD001 limits the development of tumour and causes the self-destruction of tumour cells.

Based on these results a clinical trial, funded by Novartis, has started in the United States to evaluate the efficacy of the combination of these two inhibitors of mTOR in humans. The study coordinator, Sara Kozma, noted that

"because rapamycin and its derivatives are already approved for the treatment of other diseases, their combination to BEZ235, would be a rapid strategy to test the efficacy of this drug and fast track its approval for clinical use."

Ref :1. http://www.idibell.cat/modul/news/en/362/combination-of-two-drugs-reverses-liver-tumours
2.http://stm.sciencemag.org/content/early/2012/04/27/scitranslmed.3003923

Researchers find promising drugs that could lead to first antidote for radiation exposure

University of Virginia School of Medicine researchers have identified promising drugs that could lead to the first antidote for radiation exposure that might result from a dirty bomb terror attack or a nuclear accident such as Chernobyl.

Some of the compounds, including the drug rapamycin, have previously been shown toextend life in organisms such as worms and flies, though it's unknown if they would have the same benefit in humans. UVA's research suggests that these compounds, or similar drugs, might counter the deadly effects of ionizing radiation.

 rapamycin

Currently there is no treatment for people exposed to lethal doses of radiation; doctors can only try to ease their suffering until death. "If you're exposed to a very, very high dose, it's rapid deterioration and immediate death," explained John S. Lazo, PhD, of UVA's Department of Pharmacology. "It's the lower doses that people - particularly governments - are concerned about. The type of exposure that might result from a dirty bomb or a nuclear accident. How do we alleviate the effects? What's the antidote? Right now, we just don't have anything."

Innovative Approach

Lazo and his colleague Elizabeth R. Sharlow, PhD, screened a library of more than 3,400 existing drugs, vitamins and other compounds to identify ones that might help cells withstand the effects of radiation exposure. The goal was to keep stem cells - the cells that produce the various cell types in the body - alive long enough to repair the damage caused by radiation.

"We wanted to find already approved drugs that would potentially keep stem cells, or progenitor cells, alive after radiation exposure," Sharlow said. "That's very much of interest to the NIH [National Institutes of Health] right now: How can we keep those se

lf-renewing populations alive so they can actually help heal the effects of radiation exposure?"

After they identified potential leads, Sharlow created 3D computer models to compare the substances' chemical structures. That analysis identified a cluster of promising compounds with similar structures - a tantalizing lead in the quest for an antidote. "If you're a drug hunter, the way we are, this is really cool information," Lazo said. "Because you can say, 'Now I will look in the universe of 40 million compounds. What else looks like that? Are they useful?'"

He noted that it is unlikely any one drug or compound will work on its own. "A lot of us in this field think it will be a cocktail of things you take," he said. "And if you think you need cocktails, you need the individual ingredients. That's why we think this is pretty important - because it's providing new ingredients for that cocktail."

FDA approves Afinitor drug for tuberous sclerosis complex

We know that Everolimus (RAD-001), marketed by Novartis under the tradenames Zortress (USA) and Certican (Europe and other countries) in transplantation medicine and Afinitor in oncology is the 42-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an mTOR (mammalian target of rapamycin) inhibitor. It is currently used as an immunosuppressant to prevent rejection of organ transplants. Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers. The FDA has approved everolimus for the treatment of advanced kidney cancer on March 30, 2009 and for organ rejection prophylaxis on April 22, 2010. Now the same drug has been approved for Tuberous sclerosis or tuberous sclerosis complex (TSC a rare, multi-system genetic disease that causes benign tumours to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin ) ….more

Lovastatin-synthesizing enzyme successfully reconstituted...

Lovastatin is a member of the drug class of statins, used for lowering cholesterol (hypolipidemic agent) in those with hypercholesterolemia and so preventing cardiovascular disease. Lovastatin is a naturally occurring drug found in food such as oyster mushrooms and red yeast rice. When I was working with a Banglore based company (Biocon), they did try this compound and I think the company is marketing this drug now. As for as my knowledge goes there were two ways to synthesise 'biosynthesis using Dield-Alder catalyzed cyclization' & 'biosyntheis using broadly specific acyltransferase'

Dield-Alder catalysed cyclisation : In vitro formation of a triketide lactone using a genetically-modified protein derived from 6-deoxyerythronolide B synthase has been demonstrated. The stereochemistry of the molecule supports the intriguing idea that an enzyme-catalyzed Diels-Alder reaction may occur during assembly of the polyketide chain. It thus appears that biological Diels-Alder reactions may be triggered by generation of reactive triene systems on an enzyme surface.

Biosynthesis using broadly specific acyltransferase : It has been found that a dedicated acyltransferase, LovD, is encoded in the lovastatin biosynthetic pathway. LovD has a broad substrate specificity towards the acyl carrier, the acyl substrate and the decalin acyl acceptor. It efficiently catalyzes the acyl transfer from coenzyme A thoesters or N-acetylcysteamine (SNAC) thioesters to monacolin J. The biosynthesis of lovastatin is coordinated by two iterative type I polyketide syntheses and numerous accessory enzymes. Nonketide, the intermediate biosynthetic precursor of lovastatin, is assembled by the upstream megasynthase LovB (also known as lovastatin nonaketide synthase), enoylreductase LovC, and CYP450 oxygenases.

Recently more interesting out come from a group of UCLA researchers is that, for the first time thy have successfully reconstituted in the laboratory the enzyme responsible for producing the blockbuster cholesterol-lowering drug lovastatin. As per the claim by the researchers, the lovastatin-synthesizing enzyme is one of the most interesting but least understood of the polyketide synthases, which are found in filamentous fungi and which play a crucial role in the synthesis of "small molecule natural products" — pharmacologically or biologically potent compounds produced by living organisms, many of which are the active ingredients in pharmaceuticals.

This finding is of great significance because commonly used antibiotics, such as tetracycline, are produced by polyketide synthases. Polyketides represent a class of 7,000 known structures, of which more than 20 are commercial drugs, including the immunosuppressant rapamycin, the antibiotic erythromycin and the anticancer drug doxorubicin. In their study studied the enzyme that makes a small-molecule precursor to lovastatin. The real difference about this enzyme, is its extraoridnarily large size in comparison to all other enzymes so for studied. As per the claim by the lead researcher Dr. Yi Tang, "It's one of the largest enzymes ever to be reconstituted in a test tube. It is 10 times the size of most enzymes people study & the enzyme has seven active sites and catalyzes more than 40 different reactions that eventually result in an important precursor to lovastatin. Hope with this remarkable achievement, one can prepare many natural products in the lab in the days to come.

Ref : http://www.newsroom.ucla.edu/portal/ucla/ucla-engineering-researchers-have-111812.aspx

Matcha green tea kills breast cancer stem cells

MATCHA, the Green Tea packed with antioxidants, is often hailed as containing properties which prevent disease.

Scientists in Salford, UK have shed a ray of light on the claim by testing it on cancer stem cells - with surprising results.

In research published in the journal Aging, a team from the Biomedical Research Centre at the University of Salford, used metabolic phenotyping on cell lines of breast cancer stem cells and found that Matcha "shifted cancer cells towards a quiescent metabolic state" and stopped their spread at a relatively low concentration (0.2 mg/ml).

They also found that the signaling pathways that promote cancer stem cells indicated that Matcha "strongly affected mTOR signals, weakening components of the 40S ribosome. This raised the possibility that Matcha could be used in place of chemical drugs such as rapamycin.

Michael Lisanti, professor of translational medicine at the center, explained: "Matcha green tea is a natural product used as a dietary supplement with great potential for a range of treatments. But, the molecular mechanism underpinning all that remains largely unknown.

"By using metabolic phenotyping, we found that the tea is suppressing oxidative mitochondrial metabolism - in other words it is preventing the cells from 're-fuelling' and therefore they become inactive and die.

"The effects on human breast cancer cells were very striking; the active ingredients in matcha having a surgical effect in knocking out certain signaling pathways.

"Our results are consistent with the idea that Matcha may have significant therapeutic potential, mediating the metabolic reprogramming of cancer cells."

The team who specialize in identifying non-toxic methods of killing cancer stem cells recently found that Earl Grey tea ingredient, Bergamot kills cancer cells and works as an anti-cholesterol agent.

Ref : https://www.salford.ac.uk/news/articles/2018/green-tea-prevent-cancer-cells-from-refuelling

RADIANT-3 study results show everolimus significantly extends progression-free survival in patients with advanced pancreatic neuroendocrine tumors...

We know that Everolimus (RAD-001, marketed by Novartis under the  tradenames Zortress (USA) and Certican (Europe and other countries) in transplantation medicine and Afinitor in oncology) is the 42-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an mTOR (mammalian target of rapamycin) inhibitor. It is currently used as an immunosuppressant to prevent rejection of organ transplants. Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers.

The FDA has approved everolimus for the treatment of advanced kidney cancer on March 30, 2009 and for organ rejection prophylaxis on April 22, 2010. Now Novartis Pharmaceuticals Corporation announced that the  Phase III study of Afinitor® (everolimus, see structure) tablets plus best supportive care met its primary endpoint, showing the drug significantly extended progression-free survival, or time without tumor growth, in patients with advanced pancreatic neuroendocrine tumors (NET). The study, RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors), is part of the largest clinical trial program of its kind. 

Everolimus is approved under the trade name Afinitor® (everolimus) tablets for the treatment of patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.  

As  per the claim by   Herve Hoppenot, President, Novartis Oncology, Everolimus was developed to inhibit the mTOR protein, which is a critical target in treating various cancers, including NET. Results from RADIANT-3 demonstrate that everolimus has the potential to become an important treatment option for patients with advanced pancreatic NET, where there is a major unmet need.

"These study results will serve as the basis of worldwide regulatory filings for everolimus and bring us one step closer to our goal of offering these patients a new therapy."...says Herve Hoppenot...

Ref : http://www.novartis.com/newsroom/media-releases/en/2010/1421290.shtml

Matcha green tea kills breast cancer stem cells

MATCHA, the Green Tea packed with antioxidants, is often hailed as containing properties which prevent disease.

Scientists in Salford, UK have shed a ray of light on the claim by testing it on cancer stem cells - with surprising results.

In research published in the journal Aging, a team from the Biomedical Research Centre at the University of Salford, used metabolic phenotyping on cell lines of breast cancer stem cells and found that Matcha "shifted cancer cells towards a quiescent metabolic state" and stopped their spread at a relatively low concentration (0.2 mg/ml).

They also found that the signaling pathways that promote cancer stem cells indicated that Matcha "strongly affected mTOR signals, weakening components of the 40S ribosome. This raised the possibility that Matcha could be used in place of chemical drugs such as rapamycin.

Michael Lisanti, professor of translational medicine at the center, explained: "Matcha green tea is a natural product used as a dietary supplement with great potential for a range of treatments. But, the molecular mechanism underpinning all that remains largely unknown.

"By using metabolic phenotyping, we found that the tea is suppressing oxidative mitochondrial metabolism - in other words it is preventing the cells from 're-fuelling' and therefore they become inactive and die.

"The effects on human breast cancer cells were very striking; the active ingredients in matcha having a surgical effect in knocking out certain signaling pathways.

"Our results are consistent with the idea that Matcha may have significant therapeutic potential, mediating the metabolic reprogramming of cancer cells."

The team who specialize in identifying non-toxic methods of killing cancer stem cells recently found that Earl Grey tea ingredient, Bergamot kills cancer cells and works as an anti-cholesterol agent.

Ref : https://www.salford.ac.uk/news/articles/2018/green-tea-prevent-cancer-cells-from-refuelling

Improved efficacy of tuberculosis vaccine ?

We know that BCG (Bacille Calmette-Guérin) is a live but weakened form of a bacterium, M. bovis, which causes tuberculosis in cattle. It is sufficiently related to the human pathogen to stimulate production of specialized immune cells that fight off TB infection when it is injected into a person as a vaccine. The bacilli have retained enough strong antigenicity to become a somewhat effective vaccine for the prevention of human tuberculosis. At best, the BCG vaccine is 80% effective in preventing tuberculosis for a duration of 15 years, however, its protective effect appears to vary according to geography.

Many attempts have been made to improve the vaccine by incorporating antigens (molecular components of the bacteria) to induce a stronger immune response. However, tuberculosis and BCG have evasive mechanisms that prevent the development of stronger immune responses. We read oftenly in news paper, about the drug resistant strains and use of combined drugs. Now thanx to the two research groups from UT Health Science Center at Houston. The importance of this research is in the fact that the two groups investigated mechanisms by which BCG evades immune stimulating mechanisms and devised two means to neutralize them.

1. scientists used genetically-modified organisms and
2. a drug used for organ transplantation (Rapamycin, see the structure)to block BCG's evasive mechanisms, causing it to induce stronger immune responses.

This dual approach to the BCG vaccine was associated with a tenfold increase in the number of TB organisms killed and a threefold increase in the duration of protection in tests with an NIH-approved mouse model, Dr. Jagannath said.

The research is of great importance because of the fact that "it has countered the ability of TB organisms to subvert immunization", (Tuberculosis hides in cells so the antigens are not recognized by the immune system. The BCG vaccine also does the same thing). The role of the drug is of great importance, i.e., it modulates the movement of particles in cells, would cause BCG antigens to enter pathways leading to improved immunization. I would say one more significant contribution(or else one more serendipity !) of the drug apart from bieng used in 1. treatment of cancer and inflammation 2. in significantly reducing the frequency of acute kidney transplant rejection.

Though further research to substantiate the claim is essential. Its a good beginning in this direction for the improved efficay of the vaccine.. Congrats Dr. Jagannath and group.. More...