In search of telomerase Inhibitors

Telomerase: Friend and foe

Maxim Rousseau, Polit.roo

In 2009, the Nobel Prize in Physiology or Medicine was awarded to Elizabeth Blackburn, Carol Greider and Jack Szostack, who discovered the enzyme telomerase. In recent years, telomerase has been constantly in the focus of attention of researchers around the world. It is seen as the key to the mechanisms of aging, and the reason for the unstoppable proliferation of tumor cells. The latter fact was the reason that the phrase "telomerase inhibitors" began to appear regularly in the headlines of articles devoted to cancer therapy.

What is telomerase? We remember that cell division begins with the doubling of its chromosomes containing genetic material. This doubling is provided by a special enzyme – DNA polymerase. This is a protein whose function is to move along the DNA chain to synthesize another similar chain. But here, it turns out, there is a problem. DNA polymerase cannot begin its work from the very tip of the chromosome. It acts as if slightly retreating from the beginning of the DNA chain. Therefore, with each doubling (and therefore with each cell division), part of the DNA is lost without falling under the action of DNA polymerase. If the lost area contained valuable genetic information, for example, genes that determine the synthesis of important proteins, then such a loss would not end well for the cell. Therefore, telomeres are located at the ends of chromosomes (Greek. telos "end", meros "part") – non-coding sections. It is they who gradually contract with each cell division. In humans and other vertebrates, telomeres contain a repeatedly repeated sequence of six nucleotides – TTAGGG (two thymines, adenine, three guanine).

But gradually, after more and more cycles of division, telomeres will shrink more and more. And then the moment will come when the shortening of the chromosome will begin to affect. Then the cell ages. There is a special protein in cells that can repair broken chromosomes. But if the ends of the chromosomes lose their telomeres, then this protein "takes" them for broken parts and can connect different chromosomes together. When a certain amount of such damage accumulates in the genome, a program of apoptosis, a mechanism of cell death, is launched in the cell.

American physician Leonard Hayflick (Leonard Hayflick) back in the 60s, when no telomeres were known, noticed that human cells die after passing approximately 50 cycles of division. This number is called the Hayflick limit. When researchers learned about telomeres, the mechanism of occurrence of this limit became clear. For each division, the chromosome loses about 3-6 nucleotides, and after 50 divisions, the losses become critical.

However, there are cells in the body that should not age and die after 50 divisions. These are the cells of the sexual line. They must multiply, give rise to a new organism: all its somatic and germ cells, then repeat it again and again. How can they overcome the Hayflick limit? This is where a special enzyme, telomerase, appears on the scene.

Telomerase is ingeniously arranged: it has a protein part and an RNA molecule. Telomerase RNA is surrounded by a protein and serves as a template, according to which the protein attaches new sections to the telomeres of the chromosome, the same TTAGGG sequences. As a result, telomeres lengthen again, and cellular aging stops. A cell equipped with telomerase is capable of an infinite number of divisions.

In ordinary cells of our body, telomerase is inactive. It acts only in embryonic stem cells, which give rise to all other types of cells, and in germ cells, the descendants of which will live in the organisms of descendants. However, there are cases when telomerase shows its activity completely out of place.

It turns out that telomerase is active in the cells of most tumors. And therefore it provides them with the opportunity to repeatedly share. An illustrative example of the immortality of tumor cells is the HeLa cell line, which is used in cancer research. Her cells were obtained in 1951 in Baltimore from a patient Henrietta Lacks (Henrietta Lacks, the name HeLa was given in honor of her), who suffered from cervical cancer. For more than sixty years, the descendants of these cells have been living and dividing in hundreds of laboratories in different countries. When telomerase is active, no Hayflick limit is scary.

Since telomerase allows cancer cells to divide endlessly, the doctor's task is to "turn off" telomerase. Then the telomeres in cancer cells will shorten again, after the threshold number of divisions, the cells will die, and tumor growth will stop. So, telomerase inhibitors are needed. Recall that inhibitors are substances that slow down or stop the course of a chemical reaction.

Among the companies of the biomedical technologies cluster of the Skolkovo Foundation, Onkobiotech LLC is developing in this direction.

In order to successfully compete in the race with many other developers who are also busy selecting telomerase inhibitors, a number of sequential steps are needed. First, among the many substances, those that may have the desired property are selected. That's why scientists around the world are looking for the most effective inhibitors that will stop the activity of telomerase in tumor cells.

It should be borne in mind that the mechanism of action of telomerase inhibitors may be different. Some substances disrupt the structure of the RNA component of telomerase. Then the enzyme, devoid of a template, cannot create new telomere sites. Others affect the protein part, in this case the template in the form of an RNA molecule is preserved, but the mechanism of its use is violated. When a potentially promising substance is found, it is necessary to check its other characteristics. For example, toxicity to body cells. After all, if an inhibitor stops the growth of tumor cells, but at the same time disrupts the work of other organs, it is no good.

After the candidate substance has passed the primary selection, it is time for experiments to test its effectiveness. First, they are carried out, as biologists say, in vitro, that is, on a cell culture, and not in a living organism. These may be cells of the HeLa line already mentioned, or another culture of tumor cells. If the inhibitor successfully suppresses their reproduction, you can proceed to the next stage of testing.

Researchers begin experiments in vivo when animals are used to test the effectiveness of the drug. Most often, mice act in this role. For research in the field of oncology, special genetic lines of mice have been derived, which most often have oncological diseases. Biologists also often resort to transplantation of tumor cells into the body of a healthy mouse (such a tumor is called "vaccinated"). This may be necessary when it is necessary to work with a specific type of tumor cells. With a successful transplant, the transplant begins to grow, turning into a tumor. After receiving a grafted tumor, therapy is started with a telomerase inhibitor. If the substance manages to suppress the growth of a tumor in the human body, they go through this stage of testing. At the moment, Oncobiotech LLC is working on two new classes of telomerase inhibitors, conducting their tests on laboratory animals.

Portal "Eternal youth" http://vechnayamolodost.ru 18.04.2014