Leave the tumor without glutamine
Glutamine blockade helps the body fight cancer
Polina Gershberg, Naked Science
Scientists from the Johns Hopkins Center for Medical Research have developed a compound that can slow down tumor growth, change its microenvironment and promote the appearance of highly active antitumor lymphocytes. An article about this was published in the journal Science (Leone et al., Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion).
A new substance codenamed JHU083 is a prodrug form (a substance that is transformed into a drug already in the body) of 6–diazo-5-oxo-L-norleucine (DON), a non-standard amino acid isolated from bacteria of the genus Streptomyces. Due to a certain structural similarity with glutamine, DON is able to disrupt its metabolism by blocking the active centers of enzymes.
Glutamine plays an important role in tumor metabolism. This amino acid is present in all tissues of the body and is a precursor of ATP – the main source of energy for biochemical processes. Cancer cells divide intensively and can at the same time use glutamine as the main "fuel" for growth. Therefore, blocking the oxidation of glutamine can help in the fight against cancer.
Although glutamine can utilize any cells, the prodrug DON is aimed specifically at tumor cells, because, according to scientists, they are "the hungriest." But the advantage of the new drug is not only in its selective action: metabolic therapy with DON has a certain immunotherapeutic effect, positively affecting the antitumor properties of T-lymphocytes.
The structure of the molecules DON (top) and glutamine (bottom) – VM.
Scientists tested JHU083 on mice with melanoma, lymphoma and colon cancer. The use of this substance reduced tumor growth and increased the survival rate of mice at various stages of the disease, and some rodents even managed to be cured completely. But the most interesting thing was that when the tumor cells were reintroduced, the body of the recovered mice rejected them. The researchers suggested that under the influence of JHU083, immune memory was formed in animals, thanks to which lymphocytes immediately recognized mutated cells.
It turned out that cancer cells and immune system cells reacted differently to glutamine blockade. The use of JHU083 led to the depletion of tumors and cells in their microenvironment, but made T-lymphocytes more active. "By blocking the metabolism of glutamine, we made these cells more stable, more like immune memory cells," says lead author of the study Jonathan Powell.
Scientists have also found that the use of prodrugs increases the effectiveness of adoptive immunotherapy, a treatment method in which patients are injected with specially grown T–lymphocytes in the laboratory to enhance the immune response. In subsequent studies, Powell and his colleagues want to study how JHU083 is combined with various types of immunotherapy, and find out whether certain tumors can overcome the "metabolic trap" created by the new drug.
Portal "Eternal youth" http://vechnayamolodost.ru