Enzyme inhibitor can slow tumour growth

A research team from Friedrich Schiller University Jena, together with researchers from the University Medical Centre Mainz, the University of Regensburg and the IRCM in Montreal (Canada), has discovered a novel approach to treating malignant tumours of the lymphatic system. As the team led by PD Dr Christian Kosan from the Institute of Biochemistry and Biophysics shows, the treatment of certain B-cell lymphomas with the compound „Marbostat 100“, an enzyme inhibitor, leads to a significant slowdown in tumour cell growth. The researchers present their results in the scientific journal „Oncogene“.

B-cell lymphomas are tumours of certain immune cells (B lymphocytes). These cells, which belong to the white blood cells, normally produce antibodies and are essential for the body's effective immune defence. When B lymphocytes turn into tumour cells, a specific gene called „MYC“ is often involved, says Christian Kosan. „This gene initially stimulates the cells to grow and divide faster, which can lead to further mutations and ultimately to tumour formation.“

Transcription factor „Myc“

The protein encoded by „MYC“ „Myc“ is a so-called transcription factor. „It binds to the DNA of a cell and thus regulates the activity of its target genes“, explains Kosan, who has been researching „Myc“ and its functions for a long time. A large number of human genes are directly or indirectly regulated by „Myc“. In tumours, such as aggressive B-cell lymphomas, the amount of „Myc“ is greatly increased. „Our aim was therefore to specifically block the function of „Myc‘ and thus downregulate the accelerated cell division of the tumour cells“, says Christian Kosan. As the „Myc“-protein is difficult to access even for active substances – it is relatively small and offers only a few specific docking sites on the surface for other molecules –, the researchers used a diversion: They did not target „Myc“ directly, but an enzyme that interacts with „Myc“ and regulates its function.

In their study, the team led by Christian Kosan showed that the specific inhibition of this enzyme (histone deacetylase 6) leads to a significant reduction in the concentration of „Myc“ in the tumour cells. The researchers treated human B-cell lymphoma cell lines with the enzyme inhibitor „Marbostat 100“ and found that four out of five tumour cell lines died. „We were also able to show that the ‚Myc‘proteinß is degraded in the tumour cells depending on the concentration and treatment period of the enzyme inhibitor“, says Kosan. And what's more: in trials with mice who develop B-cell lymphomas and die due to a particular mutation, treatment with „Marbostat 100“ led to a significantly longer life expectancy. Of 15 animals with tumours, 14 survived the entire study period.

Christian Kosan and his colleagues now want to apply the findings to other types of tumours. „We already know that &sbdquo;Myc‘ plays a role not only in B-cell lymphomas, but also in many other types of cancer.“ The researchers therefore want to investigate whether the use of „Marbostat 100“ could also be suitable for the treatment of other tumour cells. The long-term goal is to develop a combination therapy for the treatment of aggressive types of cancer. Up to now, B-cell lymphomas have been treated with aggressive chemotherapeutic agents, but these usually have equally strong side effects. „We want to try to use therapeutics such as the enzyme inhibitor ‚Marbostat 100‘ to slow down tumour growth in such a way that the chemotherapeutics can be administered in lower doses or over a shorter period of time and therefore fewer side effects can be expected“, says Christian Kosan.

Source: LABO from 22 November 2022