Researchers study new immunogenic properties of already existing anti-cancer drugs

The world scientific community is waging a difficult and prolonged war on cancer. New research in the field of immunogenic cell death can extend the area of drugs application and ensure patients' protection from relapse after therapy.

Cancer treatment is not just the removal of the tumor cells from the body, and chemotherapy. The doctors' aim is to provide a scenario that would prevent tumor cells from proliferating and causing a new disease.

For many years, scientists at the Lobachevsky State University of Nizhny Novgorod and the University of Ghent (Belgium) have been engaged in research aimed to minimize the harm to the body after cancer treatment and have been looking for new approaches to treating cancer patients. 

The project, supported by a grant from the Russian Science Foundation and headed by Dmitry Krys'ko, leading researcher of the Lobachevsky University's Institute of Biology and Biomedicine, professor at Ghent University, has yielded its first major results.

According to Professor Dmitry Krys'ko, the existing anti-cancer therapy (chemotherapy, radiation therapy and photodynamic therapy) causes great damage to the body as a whole, while his team's research is aimed at the stimulation of immunogenic cell death, which not only minimizes the damage, but also enhances the efficacy of treatment by involving the body's resources in the fight against cancer.

In this study, we tested some drugs for anticancer therapy based on photodynamic treatment and investigated their new immunogenic properties. We can say that not only the external impact will be used to fight cancer, but also the body itself will engage in the fight by triggering the reactions of the adaptive immune response.

The concept of immunogenic cell death (ICD) includes a programmed death of cancer cells with subsequent release of molecules that give a danger signal to the immune system. We tested the drugs that are already used in cancer therapy, and enhanced the action of these agents."

Dmitry Krys'ko, leading researcher of the Lobachevsky University's Institute of Biology and Biomedicine, professor at Ghent University

The study employed a number of methods and approaches that were used in in vitro and in vivo experiments. At the laboratories of Lobachevsky University and the University of Ghent, researchers studied how substances accumulate in the cell, analyzed cell death types when cells were exposed to photosensitizers, and revealed molecular mechanisms of the phenomena that occur to the cells in the process of their death.

"In this study, we examined the cellular-level response of dendritic cells (immune system components) in their interaction with cancer cells that were exposed to photodynamic therapy (PDT) and proved that photodynamic therapy can activate the body's own immune response," said Victoria Turubanova, research assistant of the Department of General and Medical Genetics at the UNN Institute of Biology and Biomedicine.

The researchers have examined additional aspects of the use of existing drugs for developing new cancer protocols based on the stimulation of the immune system. Such variants of therapy reduce the risk of metastasis and enhance the effectiveness of the patient's recovery.

A series of experiments on laboratory mice was performed, resulting in an important conclusion that the cellular vaccine prepared from dying cancer cells protects the mouse from cancer by preventing tumor development in the body.

Based on the results obtained, the researchers have published their article "Immunogenic cell death induced by a new photodynamic therapy based on Photosens and Photodithazine" in the BMC Journal for ImmunoTherapy of Cancer (with the impact factor of 8.67), which describes new variants of photosensitizers that cause immunogenic cell death of cancer cells.

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Lobachevsky University

IIT Hyderabad researchers unravel functioning of DNA repair proteins

Researchers are seeking to understand the workings of the DNA damage repair proteins. Certain types of chemicals produced naturally in the body can cause damages in DNA and if not fixed fast, may trigger cell death.

Researchers have unraveled the working of a protein that repairs damaged DNA.

Nature has evolved techniques to not only protect DNA, but also to repair damaged DNA so that catastrophic damage can be averted. In humans, one such repair mechanism involves activation of a special class of proteins called 'DNA' repair proteins.

With increasing awareness of the impact of DNA damage on almost all diseases and maladies, there is a worldwide effort to understand how these repair proteins work, both as an academic exercise and as the foundation for therapeutic interventions.

The results of the study has been published recently.

What makes matter a living being, be it a bacterium or man is the DNA. DNA is the file blueprint of the life-form and encodes the directions that the life-form must take in order to become bacterium, rose, lion or man. It is this essential for the survival of every cell and is usually kept well protected within the nucleus of cells and in some non0nuclear parts like the mitochondria.

Any damage to DNA can result in outcomes that can range from unperceivable mild changes, such as the sudden appearance of a harmless mole, to catastrophic diseases, such as cancer. The retention of DNA integrity is therefore essential for proper function and survival of all organisms. Protection of DNA is daunting because of the possibility of damage by external sources and the intrinsic instability of DNA itself.

" Our laboratory at IIT Hyderabad seeks to understand the working of the DNA damage repair proteins. Certain types of chemicals produced naturally in the body can cause damages in DNA and if not fixed fast, may trigger cell death", explains Dr. Anindya Roy.

Researchers discovered mechanism by which these DNA repair proteins assemble when DNA is under threat. They studies the action of one specific protein called alkB homolog 3 or ALKBH3. It has been known that ALKBH3 repairs alkylated DNA containing 1-methyladenosine and 3.methylcytosine through oxidative demethylation, but the mechanism has hitherto remained unclear.

The researchers unraveled the mechanism by which ALKBH3 brings about demethylation.

We've found that ALKBH3 has a direct protein-protein interaction with another protein called RAD51C and this interaction stimulates ALKHB3-mediated repair of methyl-adduct located within 3'-tailed DNA adds the Dr. on the technical aspects of their discovery.

The team is fascinated by the universality of the mechanism-- it is just as applicable to the bacterium as it is to the humans. " The knowledge gained from our studies might, in the long term, be beneficial from a cancer therapeutic perspective", hopes Dr. Roy, as the team proceeds with work on understanding how DNA repair works.

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Saffron can fight liver cancer

It may be an expensive spice but you cannot put a label or price on health, said a Prof. who has researched a breakthrough in the properties of saffron in fighting liver cancer.

The Prof. said that researchers have investigated and found saffron to have anti-liver cancer properties.

"Safranal, a major biomolecule of the golden spice saffron arrests and stops the cancer cell division at two different stages," he said.

"It can now be made into drugs and we are looking into whether the same can be used to fight breast and colorectal cancers as well," said the Prof.

The researchers have been working on this project since 2011 when they first published the research in the Journal.

The study suggests a novel mechanism of anti-proliferative activity of safranal against human liver cancer cells.

"This molecule could serve as a novel and/or adjuvant drug to treat liver cancer," said the Dr.

The work is in collaboration with experts in RNAseq analysis and System Biology from New York University Abu Dhabi and in Pharmacology from the University of Sharjah.

Hepatocellular carcinoma (HCC) accounts for about 80 per cent of all liver cancers, among top common cancers in the world and is the second leading cause of cancer death worldwide.

Poor prognoses remain the most challenging aspect of HCC therapy. Consequently, alternative therapeutics are essential to control HCC.

"Liver cancer was the fifth cause of death in the UAE but now it is at number four.this is how serious the disease is here," he said.

Saffron has 160 ingredients and the team identified the active ingredient (molecule, safranal) fighting cancer.

"The ingredient works in two ways; it stops cell division and promotes cell death," he explained.

Researchers concluded that safranal exerts its anticancer effect in HepG2 cells by inhibiting DNA repair, resulting in increased DNA damage.

"To translate this in real life, we have already done the testing on rats/mice and in humans it will be done not in the far future," he said.

"We hope we can achieve a clinical trial soon," he added. Clinical trials depend on permissions and may take from anywhere between six months to one year before being developed into a drug.

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This novel method can predict fatal heart disease

A novel method called stress cardiac MRI can not only diagnose heart disease, but can also predict which cases are potentially fatal, suggests a new research.

The study showed that predicting mortality is a key requirement for the technology to be more widely used. 

In addition, results suggest cardiac magnetic resonance (CMR) has the potential to be a non-invasive, non-toxic alternative to stress echocardiograms, catheterisations and stress nuclear exams in identifying the severity of the coronary heart disease.

"We've known for some time that CMR is effective at diagnosing coronary artery disease, but it's still not commonly used and represents less than one per cent of stress tests used in this country," said  senior author of the study.

For the study, researchers analysed data from more than 9,000 patients who underwent CMR.

The findings, showed that for patients without any history of  heart disease and at low-risk based on traditional clinical criteria, those with an abnormal CMR scan were 3.4 times more likely to die compared to patients with a normal CMR scan.

For the entire patient population, there was a strong association between an abnormal stress CMR and mortality, even after adjusting for patient age, sex and cardiac risk factors, the team found.

While non-invasive cardiac stress testing is a cornerstone in the clinical management of patients with known or suspected coronary artery disease, CMR works as well or better than other exams at identifying heart wall motion, cell death and the presence of low blood flow, said the study.

Furthermore, the technology does not require any radiation exposure, which is essential in nuclear stress tests.

"With the findings from this study suggesting that stress CMR is effective in predicting mortality, we provide a strong basis for a head-to-head study between stress CMR and other modalities," the author noted.

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Never starve yourself as it's primarily responsible for typical cell death

Are you one of those who starve yourselves for losing weight? You might want to think that again as a new study say that starvation is the main cause of typical cell death.

According to a new study, researchers have characterized the cell death process due to starvation, in which the endoplasmic reticulum plays a leading role.

.The study got published in journal Molecular and Cellular Biology."Usually, programmed cell death -- also called apoptosis -- follows a biochemical pathway related to the permeabilization of mitochondria; However, we observed that in cases of cell death due to lack of glucose, cells die in an unexpected way, following a process similar to what we would expect from an immune response," stated Dr. Cristina Muñoz-Pinedo, study`s lead author.

The study finds that in cell-death-related treatments such as chemotherapy, the mitochondrial pathway is activated.

Instead, when starved, cells activate the so-called "death receptors" on their membrane, which are normally used by the lymphocytes of the immune system to attack and destroy infected cells.

The researchers have been able to relate the activation of these membrane receptors to the endoplasmic reticulum, a cellular organelle involved in protein synthesis and lipid metabolism, as well as intracellular transport.

"Feeling the stress produced by the lack of nutrients, the reticulum send an alarm signal that triggers the appearance of death receptors in the membrane", said Dr. Muñoz-Pinedo.

"According to our in vitro results, we assume that this is how the tumor cells located in the center of a tumor -- the so-called necrotic core -- die, because there are never enough nutrients in those areas.

On the other hand, in ischemia, besides the lack of oxygen there is also cell death due to lack of glucose, so this process could also be related to the activity of the endoplasmic reticulum at a biochemical level," added the IDIBELL researcher.

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Researchers discover rescue protein that delays cell death

A team of researchers has discovered a rescue protein that delays the cell death and can offer a treatment for cancer, neurodegeneration and infection.

The study was published in journal Cell.The team has discovered how a set of proteins delays the "executioner" machinery that kills damaged or infected cells in a process called necroptosis.

The scientists believe these finding may have wide clinical implications if researchers can develop drugs to control the cellular rescue machinery.

Rescue treatments that prevent necroptosis in transplanted organs could reduce injury to the transplant caused by lack of oxygen, researchers said.

Drugs to rescue cells from necroptosis could also help prevent injuries to tissue deprived of blood by heart attack and stroke. In such cases, restoring blood flow and oxygenation triggers inflammation that kills tissue.

The scientists said cell-rescuing drugs could also thwart cancer spread by protecting blood vessel cells from being killed by tumor cells.

Tumor cells escape the bloodstream to spread in the body by killing blood vessels. Blocking the rescue machinery might also prove useful in treating cancers, by enhancing death of cancer cells by necroptosis.

In treating neurodegenerative disorders such as ALS--also known as Lou Gehrig`s Disease--activating the rescue machinery could help prevent death of brain cells.

In treating viral infections such as influenza, rescue treatment could extend the life of cells infected by the virus, so that the body`s immune system would be more strongly alerted to fight the infection.

Scientists knew that the "executioner" in necroptosis was a protein called MLKL.When MLKL is activated by the necroptosis machinery, it triggers a piercing of the plasma membrane surrounding the cell, ultimately killing it.

However, the scientists discovered how cells could survive necroptosis.Researchers showed the plasma membrane could repair itself by forming "bubbles" of broken plasma membrane that would shed from the cell to repair the holes.

Experiments showed the set of proteins called ESCRT-III was responsible for forming the repair bubbles. The research also revealed that ESCRT-III delayed or prevented necroptosis by repairing breaks in the plasma membrane.

The delay gave the dying cells time to release signals to alert surrounding cells to the presence of a viral infection.The investigators also discovered that activating MLKL is not a point of no return for cell survival, and that ESCRT-III could resuscitate damaged cells.In experiments relevant to transplantation, the researchers measured levels of activated MLKL protein in tissue samples from kidneys used in transplants.

Such cells experience stress during the transplantations, and researchers suspected the cells would show signs of necroptosis.The scientists found that although MLKL was activated in the kidney cells after transplantation, the cells did not die, and this protection correlated with an increase in the levels of the ESCRT-III machinery necessary for rescue of cells with active MLKL.

Douglas Green, Ph.D., chair of the St. Jude Department of Immunology emphasized that the current findings are only "suggestive" at this point, because the experiments were done in cell cultures and tissue samples. Further studies are needed to establish that the rescue machinery functions in whole organs.

The research by Green and his colleagues will also aim at discovering the biological signals regulating ESCRT-III, to enable more precise control of the rescue machinery."Those studies could yield drugs to regulate the rescue process," Green said.

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Nutrient deprivation triggers cell death in cancers

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 Focusing their research on the kidney cancer renal cell carcinomas, the researchers discovered that majority of these cancer cells rewire their metabolism in a way that leaves them addicted to an outside nutrient called cystine.

By depriving the cancer cells of the amino acid cystine, the researchers were able to trigger a form of cell death called necrosis in mouse models of the disease.

"We found that the same machinery that makes these tumours so aggressive also makes them vulnerable to nutrient deprivation," said senior study author Jen-Tsan Ashley Chi, associate professor at Duke University School of Medicine in North Carolina, US.

"It is like we are beating it at its own game," Chi noted.

The findings appeared online in the journal Cancer Research.

Chi said the study points to a promising new approach for the treatment of renal cell carcinoma, a form of kidney cancer that has historically been very difficult to cure.

 About three-fourths of renal cell carcinoma cases are marked by a missing VHL tumour-suppressor gene, which keeps healthy cells from developing into tumours.


The researchers decided to investigate how this single genetic change could affect the metabolism and nutrient requirement of cancer cells.

They subjected the cancer cells to a nutrient deprivation test, removing each of the 15 amino acids from their growth media, one by one.

Most of the time, the cells weathered the change quite well, slowing down their growth but otherwise remaining healthy.

But the researchers found that when cystine was removed, the cells swelled up and floated to the surface, a sure sign of necrotic death.