Metformin confers anti-tumor immunity by reactivating exhausted CD8T lymphocytes

Mice inoculated with melanoma cells (MO5 expressing OVA) were treated w/o metformin(Met) from day 7, as indicated by the shadowed rectangle, and tumor growth was monitored. Metformin treated mice showed significant inhibition of tumor growth.

Anti-cancer effect of tumor infiltrating CD8+T lymphocyte (CD8TIL) is suppressed by interaction between immune-checkpoint molecules such as PD-1 and CTLA-4 expressed on CD8TIL and their ligands expressed on cancer cells, which is referred to as immune-exhaustion. Cancer immunotherapy with antibody-mediated, immune-checkpoint blockade is now promising in preventing advanced melanoma and non small cell lung carcinoma (NSCLC). Such antibody-mediated immunotherapy, however, faces their enormous financial problem and significant side effects like autoimmune diseases.

On the other hand, metformin, a safe and low cost drug prescribed for patients with type 2 diabetes, has been recognised to have anti-cancer effect. We found that CD8TIL is a target of metformin. CD8TIL inevitably undergoes immune-exhaustion, characterised by diminished production of multiple cytokines such as IL-2, TNFα and IFNγ, followed by elimination with apoptosis. Metformin is able to counter the state. Metformin, thus, blocked immune exhaustion within tumor tissues.

Mice administered metformin by free drinking water, showed significant tumor growth inhibition in 6 distinct tumor models and CD8TIL becomes resistant against apoptosis, furthermore, it begins to produce multiple cytokines. Blood concentration of metformin in those mice is almost comparable to that of type 2 diabetes patients who are taking metformin daily. Therefore, along with other cancer immuno-therapies, treatment of cancer patients with metformin may significantly improve the efficacy and have a great benefit for their prognosis.

Metformin confers anti-tumor immunity by reactivating exhausted CD8T lymphocytes

On days 7, 10 and 13, TILs were recovered from tumor masses, and CD8+ TILs were examined for Kb-OVA257–264 and Kb-TRP2180–188tetramer binding (n = 7–13) by flow cytometry analysis. The population of CD8+ TILs specific for either antigen, OVA257–264 or TRP2180–188, was significantly increased in metformin treated mice (+), compared with non-treated mice (-). The accumulation of antigen specific of CD8+ TILs is caused by inhibition of apoptosis by metformin treatment.

Provided by: Okayama University

Study reveals how diabetes drug metformin prevents, suppresses cancer growt

Considerable evidence has indicated that the drug metformin, used for more than 50 years to treat type 2 diabetes, also can prevent or slow down the growth of certain cancers; but the mechanism behind its anticancer effects has been unknown. Now a team of Massachusetts General Hospital (MGH) investigators has identified a pathway that appears to underlie metformin’s ability both to block the growth of human cancer cells and to extend the lifespan of the C.elegans roundworm, implying that this single genetic pathway plays an important role in a wide range of organisms.

“We found that metformin reduces the traffic of molecules into and out of the nucleus – the ‘information center’ of the cell,” says Alexander Soukas, MD, PhD, of the MGH Center for Human Genetic Research, senior author of the study in the Dec. 15 issue of Cell. “Reduced nuclear traffic translates into the ability of the drug to block cancer growth and, remarkably, is also responsible for metformin’s ability to extend lifespan. By shedding new light on metformin’s health-promoting effects, these results offer new potential ways that we can think about treating cancer and increasing healthy ageing.”

Metformin’s ability to lower blood glucose in patients with type 2 diabetes appears to result from the drug’s effects on the liver—reducing the organ’s ability to produce glucose for release into the bloodstream. Evidence has supported the belief that this is the result of metformin’s ability to block the activity of mitochondria, structures that serve as the powerhouse of the cell. But while that explanation appears to be fairly straightforward, Soukas explains, more recent information suggests the mechanism is more complex.

Several studies have suggested that individuals taking metformin have a reduced risk of developing certain cancers and of dying from cancers that do develop. Current clinical trials are testing the impact of metformin on cancers of the breast, prostate and pancreas; and several research groups are working to identify its molecular targets. Soukas’s team had observed that, just as it blocks the growth of cancer cells, metformin slows growth in C.elegans, suggesting that the roundworm could serve as a model for investigating the drug’s effects on cancer.

Their experiments found that metformin’s action against cancer relies on two elements of a single genetic pathway – the complex, which allows the passage of molecules into and out of the nucleus, and an enzyme called ACAD10. Basically, metformin’s suppression of mitochondrial activity reduces cellular energy, restricting the traffic of molecules through the nuclear pore. This shuts off an important cellular growth molecule called mTORC1, resulting in activation of ACAD10, which both slows the growth and extends the lifespan of C.elegans.

In human melanoma and pancreatic cancer cells, the investigators confirmed that application of drugs in the metformin family induced ACAD10 expression, an effect that depended on the function of the nuclear pore complex. Without the complete signalling pathway – from mitochondrial suppression, through nuclear pore restriction to ACAD10 expression – cancer cells were no longer sensitive to the effects of metformin-like drugs.

“Amazingly, this pathway operates identically, whether in the worm or in human cancer cells,” says Soukas, who is an assistant professor of Medicine at Harvard Medical School. “Our experiments showed two very important things: if we force the nuclear pore to remain open or if we permanently shut down ACAD10, metformin can no longer block the growth of cancer cells. That suggests that the nuclear pore and ACAD10 may be manipulated in specific circumstances to prevent or even treat certain cancers.”

The essential contribution of ACAD10 to metformin’s anticancer action is intriguing, Soukas adds, because the only published study on ACAD10 function tied a variant in the gene to the increased risk of type 2 diabetes in Pima Indians, suggesting that ACAD10 also has a role in the drug’s anti-diabetes action. “What ACAD10 does is a great mystery that we are greatly interested in solving,” he says. “Determining exactly how ACAD10 slows cell growth will provide additional insights into novel therapeutic targets for cancer and possibly ways to manipulate the pathway to promote healthy ageing.”

 

Provided by: Massachusetts General Hospital

Treating cancer with drugs for diabetes and hypertension

A combination of a diabetes medication and an anti-hypertensive drug can effectively combat cancer cells. The team of researchers led by Prof. Michael Hall at the Biozentrum of the University of Basel has also reported that specific cancer cells respond to this combination of drugs. The results of the study have now been published in Science Advances.

Metformin is the most widely prescribed drug for the treatment of type 2 diabetes. Besides its blood sugar lowering effect, it also displays anti-cancer properties. The usual therapeutic dose, however, is too low to effectively fight cancer. The research team led by Prof. Michael Hall, at the Biozentrum of the University of Basel, has now made an unexpected discovery: The anti-hypertensive drug syrosingopine potentiates the anti-cancer efficacy of metformin. Apparently, this drug combination drives cancer cells to programmed “suicide.”

Drug cocktail kills tumor cells

At higher doses, the anti-diabetic drug inhibits the growth of cancer cells but could also induce unwanted side effects. Therefore, the researchers screened over a thousand drugs for whether they can enhance the anticancer action of metformin. A favourite emerged from this screening: Syrosingopine, an anti-hypertensive drug. As the study shows, the cocktail of these two drugs is effective in a wide range of cancers.

“For example, in samples from leukaemia patients, we demonstrated that almost all tumor cells were killed by this cocktail and at doses that are actually not toxic to normal cells,” says the first author, Don Benjamin. “And the effect was exclusively confined to cancer cells, as the blood cells from healthy donors were insensitive to the treatment.”

Drugs block “juice” supply to cancer cells

In mice with malignant liver cancer, enlargement of the liver was reduced after the therapy. Also the number of tumor nodules was less – in some animals the tumors disappeared completely. A glance at the molecular processes in the tumor cells explains the drug combination’s efficacy: Metformin lowers not only the blood glucose level, but also blocks the respiratory chain in the energy factories of the cell, the mitochondria. The anti-hypertensive drug syrosingopine inhibits, among other things, the degradation of sugars.

Thus, the drugs interrupt the vital processes which provide energy for the cell. Due to their increased metabolic activity and rapid growth, cancer cells have a particularly high energy consumption, which makes them extremely vulnerable when the energy supply is reduced.

Groundbreaking step towards clinical application

By testing a range of other compounds with the same mode of action, the scientists could demonstrate that the inhibition of the respiratory chain in the mitochondria is a key mechanism. These also reduced cancer cell growth in combination with the anti-hypertensive drug.

“We have been able to show that the two known drugs lead to more profound effects on cancer cell proliferation than each drug alone,” explains Benjamin. “The data from this study support the development of combination approaches for the treatment of cancer patients.” This study may have implications for future clinical application of combination scenarios targeting the energy needs of tumor cells.

Provided by: University of Basel

Russian Scientists Develop New Method to Destroy Chemo-resistant Cancer Cells

A group of Russian scientists obtained a new anti-cancerous compound that has the ability to combat cancer cells even if they are resistant to chemotherapy.

Moscow Institute of Physics and Technology (MIPT) Professor Alexander Kiselyov who leads the research told Sputnik International about the novel substance. “The chemical compound was synthesised from an early product found in nature — parsley and dill seeds. Liquid carbon dioxide was used for extracting the needed natural components, which were then purified in the N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,” explained Prof. Kiselyov, Moscow State University graduate, who received PhD degree in synthetic organic chemistry at the Georgia State University, was a Postdoc fellow at the Ben May Department for Cancer Research of the University of Chicago and at the Columbia University and now continues to work in national medicinal chemistry, structural biology and drug development.

Through oxidation of the initial compounds, the researchers obtained “building blocks” for further systematic assembling of the target structures. “It was those structures which caught our attention due to their biologically activity and unique mechanism of influence on cell division and tubulin mega-structures,” the professor said.

Tubulin is one of the basic proteins critical for cell division. “Cancer cells are considered to be especially sensitive to the influence on tubulin. So, when treatment is used properly and accurately, cancer cells die first.” Prof. Kiselyov and his team have been working on such drugs for about a decade. Apart from numerous classes of the anti-cancerous compounds, they have also developed a highly sensitive test using sea urchin embryos. “Active and specific substances that affect tubulin in particular are easily and clearly proving their efficiency in this assay,” the researcher said. Thus, an effective synthesis of substances from easily available natural sources combined with tests on urchin embryos and panels of human cancer cells, including resistant ones, led to the identification of key material, Alexander Kiselyov concluded. “Interestingly, the substance acted most effectively against ovarian cancer cells. Our team is currently trying to discover the molecular ‘reason’ for such specificity in order to further optimise this substance, to improve its effectiveness and its ‘safety’ towards healthy cells,” he added.

It is too early to call it a breakthrough, the professor considers. The team needs to overcome few necessary barriers on the way to clinical testing. Besides proving the specific mechanism of the substance towards ovarian cancer and improving its qualities, the researchers have to conduct in vivo assays using human cancer cells transplanted into laboratory animals, as well as understand its behaviour in living systems and its toxicity.

“Our preliminary tests show that our substance is able to kill even chemotherapy resistant cells of ovarian cancer. However, despite the promising results, we have a lot of hard work in front of us,” Prof. Kiselyov told Sputnik. “Elaboration of the effective and specific treatment for clinical testing takes at least few years of research in vivo.”

‘Biological Assassin’ Cells Injected Into Brain Successfully Treats Cancer

An experimental brain-cancer treatment successfully eliminated tumors in a man’s brain, according to a report in the New England Journal of Medicine. The treatment, which involves injecting cancer-killing cells into the part of the brain that produces spinal fluid, has been called ‘striking’ and ‘remarkable’ by neurosurgeons in early-stage testing.

50-year-old Richard Grady was diagnosed with a brain tumor known as a glioblastoma, or GBM tumor. The American Brain Tumor Association describes GBM tumors as “usually highly malignant,”  and “difficult to treat.” Rare Disease Report writes that GBM tumors develop rapidly, and that the life expectancy for patients who develop a GBM tumor is 12 months, even with treatment. Grady received the typical treatment of surgery, radiation, and chemotherapy, but it proved ineffective and his cancer returned within six months. Grady was then enrolled in a clinical trial which experimented with CAR-T cell therapy, a treatment technique in which immune cells known as T-cells are modified in a lab to become “biological assassins” that seek and destroy cancerous cells. CAR-T therapy is usually used to treat blood-borne cancers, but doctors at City of Hope cancer centre in Duarte, California, believe it may also be effective against solid tumors. Initially, CAR-T therapy had limited effectiveness for Grady. His tumors continued to grow and the cancer spread to his spine. But when doctors placed a tube into Grady’s brain and injected CAR-T cells into the choroid plexus, the part of the brain that produces cerebrospinal fluid, the results were dramatic. His spinal fluid carried the specialised cells throughout his nervous system, where they attacked and destroyed the cancer. The tumors in his body shrank dramatically after three treatments, disappearing entirely after ten. Although Grady’s cancer has since recurred, City of Hope neurosurgery chief Dr. Benham Badie has been very impressed with Grady’s reception to the new therapy. Patients in his position typically live for only a few weeks, so Grady, to have lived for over a year and a half, is impressive. The side effects of the treatment, including headaches, muscle aches, and fatigue, were reported to be manageable. “I believe these recent results show we have a potential breakthrough treatment that may have a remarkable impact on patients with malignant brain tumors,” said Badie.

Grady is one of nine to be treated at City of Hope with CAR-T cells dripped directly into the brain via a tube. Badie said that seven of the nine subjects responded favourably to the treatment. “The most exciting thing about our study is that it proves a better treatment may be attainable,” said study lead Dr. Christine Brown. She called the successes of their experiment against GBM tumors “unheard of.”

Co-author Dr. Stephen Forman called the research promising, suggesting that it could be used to treat a variety of cancers.”Our CAR-T program here is focused not only on leukaemia, lymphoma and myeloma, but also on solid tumors including breast cancer, liver cancer and brain cancer, as a way to try to make effective immunotherapy options for difficult-to-treat cancers,” he said. City of Hope is only one of a handful of cancer centres in the United States studying the use of CAR-T as a treatment against solid tumors.

Revolutionary Machine Identifies Cancer, Other Diseases from a Single Breath

A team from the Israel Institute of Technology has developed a device that can identify diseases such as multiple forms of cancer, Parkinson’s disease, and multiple sclerosis from a single breath . While the machine is still in the experimental stages, it has a high degree of promise for use in non-invasive diagnoses of serious illnesses.

The international team demonstrated that a medical theory first proposed by the Greek physician Hippocrates some 2400 years ago is true, certain diseases leave a “breath-blueprint” on the exhalations of those afflicted. The researchers created a prototype for a machine that can pick up on those diseases using the outgoing breath of a patient. The machine, called the Na-Nose, tests breath samples for the presence of trace amounts of chemicals that are indicative of 17 different illnesses.

“Each of these diseases is characterized by a unique fingerprint, meaning a different composition of these 13 chemical components,” said study lead Prof. Hossam Haick. “Just as each of us has a unique fingerprint that distinguishes us from others, each disease has a chemical signature that distinguishes it from other diseases and from a normal state of health. These odor signatures are what enables us to identify the diseases using the technology that we developed.”

Haick’s team has collected breath samples from 1400 people since 2011. Most instruments are not sensitive enough to measure the levels of chemicals associated with the specific disease, but the Israeli team’s device uses an “artificially intelligent nano-array” of gold nano-particles and carbon nano-tube sensor technology to collect data, which is then analysed by a spectrometer that accounts for factors including age and gender.

Developers of Na-Nose report an 86-percent success rate in trials. The device would need to be at least 99 percent accurate to be used in clinical diagnoses. Many diseases see a significant increase in survivability if diagnosed early, according to Haick, who pointed out that the survival rate of lung cancer increases from 10 percent to 70 percent with early diagnosis.

Cancer is typically diagnosed with a lab test of bodily fluids, like blood or urine, an imaging procedure like a CT Scan or PET Scan, and finally a biopsy of the potentially affected area. The process can be time-consuming, expensive, and requires multiple trips to various medical facilities. Haick believes Na-Nose could lead to much more rapid diagnosis and an immediate start to treatment, if the technology is perfected. It could even be used to test those at high risk in certain conditions whether or not they are ill.  Haick also said that a commercial device meant to test for strep throat and influenza is in the testing stages. While Na-Nose is far from the first breath device meant to test for diseases, it is the first to test for multiple diseases at once.

Aquatone – The universal healing tool

Is there a universal method to restore health, prevent diseases and slow down the aging process? Is there something that could help heal diseases and disorders of the joints, spine, chronic problems of various kinds, allergies, insomnia, high blood pressure or reducing wrinkles and aging? Can athletes recover their strength after intense exercise, boost performance thanks to this method? Is there a universal and holistic therapy method?

Yes, there is such a method. It is based on a discovery made by Russian scientists in 1995. They discovered the “language” of the body’s water molecules. The water molecules are resonating with different frequencies; these vibrations were found to be very weak with a wavelength of nearly a centimeter.

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Energy in motion vibrates in a certain way with certain frequencies; the water molecules are part of these vibrations because the human body contains 75% water molecules. It is in this environment that all biochemical processes in the body take place, as well as metabolism and all other physical and emotional and mental event. Everything occurring in the body must be in harmony and energy Qi must flow freely. Water molecules tune into all these biological processes and thus by correcting water molecules frequencies we correct body auto-regulation and trigger self-healing forces.  In various diseases, the resonance frequencies of water molecules differ from the normal.

The discovery of water resonance waves led to the development of a treatment device called Aquatone; it emits the same frequencies specific for aquatic environment of all living organisms with an intensity not exceeding 16 × 10(-8) watts. Aquatone emits radiation which is several thousand times lower than that of a mobile phone. Despite this low intensity, Aquatone affects the body and all its biochemical processes. It is now possible to improve the body health in a simple and effective way that does not cause any side effects; now are opening enormous opportunities for public health.

Aquatone affects all organs or body parts and restore normal function in diseased and damaged systems caused by most known diseases. These results have been confirmed by over 150 scientific studies and clinical trials conducted over last 14 years. These studies are based not only on laboratory work, but also show practical results in hospitals and clinics.

Doctors confirm the high efficiency of the Aquatone therapy manifested in reduced or eliminated symptoms. The high versatility and efficiency of Aquatone therapy can be explained and demonstrated; just as simple as this: the common denominator of all diseases are abnormal frequencies of water molecules in the affected area.  Aquatone therapy has been particularly effective in restoring damaged tissue after accidents, injuries of the musculoskeletal system, burns and radiation injury with painful symptoms. This water resonance wave therapy strengthens the immune system’s ability to fight infections and various inflammations.

It should also be mentioned that sports doctors point out that Aquatone therapy aims to restore the resonance of water molecules, increasing so the physical endurance and recovery after intense physical exertion. Hidden reserves can then be mobilized without the help of drugs.

More than 150 scientific studies done worldwide prove that Aquatone is one of the most efficient therapy devices, even for serious health conditions such as MS, ALS, RLS, Alzheimer and Dementia, Cancer, Lyme disease, liver fibrosis and cirrhosis, kidney weakness, nephrotic kidneys, arthritis, arthrosis, depression, insomnia, cosmetic applications.

Learn more about how to use Aquatone by watching this video: