New enzyme targets for selective cancer therapies

Thanks to important discoveries in basic and clinical research and technological advances, the fight against cancer has mobilized into a complex offensive spanning multiple fronts.

Work happening in a University of Alberta chemistry lab could help find new and more selective therapies for cancer. Researchers have developed a compound that targets a specific enzyme overexpressed in certain cancers—and they have tested its activity in cells from brain tumours.

Chemistry professor Christopher Cairo and his team synthesized a first-of-its-kind inhibitor that prevents the activity of an enzyme called neuraminidase. Although flu viruses use enzymes with the same mechanism as part of the process of infection, human cells use their own forms of the enzyme in many biological processes.

Cairo’s group collaborated with a group in Milan, Italy, that has shown that neuraminidases are found in excess amounts in glioblastoma cells, a form of brain cancer.

In a new study, a team from the University of Milan tested Cairo’s enzyme inhibitor and found that it turned glioblastoma cancer stem cells—found within a tumour and believed to drive cancer growth—into normal cells. The compound also caused the cells to stop growing, suggesting that this mechanism could be important for therapeutics. Results of their efforts were published Aug. 22 in the Nature journal Cell Death & Disease.

Cairo said these findings establish that an inhibitor of this enzyme could work therapeutically and should open the door for future research.

“This is the first proof-of-concept showing a selective neuraminidase inhibitor can have a real effect in human cancer cells,” he said. “It isn’t a drug yet, but it establishes a new target that we think can be used for creating new, more selective drugs.”

Long road from proof of concept to drug

Proving the compound can successfully inhibit the neuraminidase enzyme in cancer cells is just the first step in determining its potential as a therapy.

In its current form, the compound could not be used as a drug, Cairo explained, largely because it wasn’t designed to breach the blood-brain barrier making it difficult to reach the target cells. The team in Milan had to use the compound in very high concentrations, he added.

The research advances our understanding of how important carbohydrates are to the function of cells. Although most of us think of glucose (blood sugar) as the only important sugar in biology, there is an entire area of research known as glycobiology that seeks to understand the function of complex carbohydrate structures in cells. Carbohydrate structures cover the surface of cells, and affect how cells interact with each other and with pathogens.

Scientists have known for decades that the carbohydrates found on cancer cells are very different from those on normal cells. For example, many cancers have different amounts of specific residues like sialic acid, or may have different arrangements of the same residues.

“The carbohydrates on the cell surface determine how it interacts with other cells, which makes them important in cancer and other diseases. So, if we can design compounds that change these structures in a defined way, we can affect those interactions,” Cairo explained. “Finding new enzyme targets is essential to that process, and our work shows that we can selectively target this neuraminidase enzyme.”

Although there has been a lot of work on targeting viral neuraminidase enzymes, Cairo’s team has found inhibitors of the human enzymes. “The challenge in human cells is that there are four different isoenzymes. While we might want to target one for its role in cancer, hitting the wrong one could have harmful side-effects,” he said.

The U of A team reached out to their colleagues in Milan who were studying the role of a specific neuraminidase isoenzyme in cancer cells isolated from patients. Cairo approached them about testing a compound his team identified last year, which was selective for the same isoenzyme.

“I expected it would do something, but I didn’t know it would be that striking. It came out beautifully,” Cairo said.

The U of A team is already working on improving the compound, and developing and testing new and existing inhibitors using a panel of in vitro assays they developed.

“We’ve been working on these enzymes for about five years. Validation of our strategy­­­—design of a selective neuraminidase inhibitor and application in a cell that overexpresses that enzyme—is an achievement for us.”

When you get the flu, viruses hijack your cells and convert them to virus-producing factories, ultimately causing cell death and infection within the body. After a virus is manufactured, it must escape the cell by binding to the plasma membrane and cutting it open. Influenza viruses accomplish this with the enzyme neuraminidase (crystallized neuraminidase shown here). Many common antiviral drugs, such as Tamiflu and Relenza, work to inhibit the activity of neuraminidase, preventing viruses from escaping and spreading.

Image by Julie Macklin and Dr. Graeme Laver.

The Beauty of Fridays, with a Note on Bird Flu

Fresh from the Christmas Party, I woke up today and headed out to go into the office. However, the weather was so perfect that I felt the need to spend just a bit of time outside before sitting in a cubicle all day, and so instead of walking to the bus stop I instead walked over to the promenade near Belcher Bay in Kennedy Town—a short, 10 minute walk from my apartment building—and sat at the waterfront enjoying the relatively warm sunshine for a bit, as well as the company of several fishermen and an elderly couple.

In the lab, things were entirely back to normal. Which is to say, I faced the usual lack of progress on my project.

In other news, there has been a notable lack of chicken in the grocery store I usually shop at recently, and I’m just now realizing that it is likely due to the H7N9, and more recept H10N8, bird flu scare that has killed several people here lately.

As an aside, the H and N designation in flu strains arise, respectively, from the neuraminidase and hemagglutinin proteins on the flu virus capsid. These proteins are extremely variable across flu types because they are highly mutagenic, but their core function in the viral “life cycle” is relatively universal: hemagglutinin binds the flu virus to the cell it is going to infect, while neuraminidase subsequently allows the release of new viruses from the infected cell.

As we sit and eat lunch every day in Queen Mary Hospital, where bird flu patients are treated, I try not to think about these things, and just focus on the black fungus, or whatever, that is in my dish for the day.

Edmonton researchers find new target for cancer therapies

See on Scoop.it - Alberta #Tech


Researchers at the University of Alberta may have helped uncover a novel method of treating glioblastoma, a type of brain cancer. Chemistry professor Christopher Cairo and his team synthesized a compound that inhibits the enzyme neuraminidase four (NEU4). Neuraminidase is found in regular cells and viruses, but is more abundant in certain types of cancer, Cairo said.


See on edmontonjournal.com

New Post has been published on http://buzzalert.org/scientists-discover-that-glioblastoma-cancer-cells-revert-to-normal-when-exposed-to-a-particular-enzyme-inhibitor-neuraminidase-is-the-enzyme-responsible-for-growth-in-many-kinds-of-brain-cancer-whe/

Scientists discover that glioblastoma cancer cells revert to normal when exposed to a particular enzyme inhibitor. Neuraminidase is the enzyme responsible for growth in many kinds of brain cancer. When blocked, the tumor cells reverted to normal, and refrained from growing.

Scientists discover that glioblastoma cancer cells revert to normal when exposed to a particular enzyme inhibitor. Neuraminidase is the enzyme responsible for growth in many kinds of brain cancer. When blocked, the tumor cells reverted to normal, and refrained from growing.



Original post | Reddit thread
New enzyme targets for selective cancer therapies

Compounds that target brain cancer have been recently developed by researchers. The team synthesized a first-of-its-kind inhibitor that prevents the activity of an enzyme called neuraminidase. Although flu viruses use enzymes with the same mechanism as part of the process of infection, human cells use their own forms of the enzyme in many biological processes.



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Published On Claire Magazine @ - http://blog.clairepeetz.com/new-enzyme-targets-for-selective-cancer-therapies/

New enzyme targets for selective cancer therapies

Compounds that target brain cancer have been recently developed by researchers. The team synthesized a first-of-its-kind inhibitor that prevents the activity of an enzyme called neuraminidase. Although flu viruses use enzymes with the same mechanism as part of the process of infection, human cells use their own forms of the enzyme in many biological processes.

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Hebrew University antibody research paves the way for new, more effective influenza drugs

Annual epidemics of seasonal influenza lead to between 250,000 and 500,000 deaths worldwide. It is known that natural killer (NK) cells that belong to the body’s innate immune system can eliminate influenza virus-infected cells. This is made possible via by one of the major NK killing receptors, NKp46, that recognizes influenza virus expressed on the infected cells. But influenza viruses have an evasion mechanism that is mediated by the neuraminidase (NA) protein, which counterattacks NKp46 recognition of infected cells and reduces its ability to eliminate them. Yotam Bar-On, a Hebrew University Ph.D. candidate in immunology and cancer research, has shown for the first time, that NA inhibitors, already commonly used to treat influenza infections, enhance the NKp46-mediated killing of infected cells. Through further research into peptide components of the NA protein, Bar-On was able to develop antibodies that can to bind the NA, in effect “tying them up” and taking them out of action…


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