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Research team clarifies molecular basis for cachexia
Chemotherapeutic agents are often used to treat cancer. They combat tumour growth, but also have a number of undesirable side effects. One of these is severe muscle wasting, known as chemotherapy-induced cachexia. This chronic disease causes uncontrollable breakdown of fat and muscle tissue as well as weight loss. However, in order to improve treatment strategies, the molecular basis must first be understood. This is where PD Dr Arnab Nayak, a scientist at the Institute of Molecular and Cellular Physiology at Hannover Medical School (MHH), comes in. With his research group ‘Chromatin and SUMO Physiology’, the molecular biologist has shown that the chemotherapeutic agent sorafenib actively remodels skeletal muscle cells and thus triggers cachexia. The work has been published in the journal ‘iScience’.
Formation and function of skeletal muscle fibres impaired
Sorafenib is used for liver cell carcinoma (HCC) and renal cell carcinoma (RCC), among others. The chemotherapeutic agent belongs to the so-called tyrosine kinase inhibitors, which attack chemical messengers that are important for tumour development. Sorafenib targets several enzymes involved in cell growth as well as the formation of new blood vessels triggered by the tumour itself, which tumours use to ensure their supply of oxygen and nutrients. At the same time, sorafenib interferes with epigenetic regulation in muscle-specific genes. Epigenetics describes mechanisms that do not influence the genes themselves, but their activity.
In this way, epigenetic processes control which genes are switched on or off and therefore also have an influence on whether and when a disease breaks out or not. Through epigenetic mechanisms, cells react to environmental influences, among other things.
In the case of sorafenib, the researchers have uncovered an unusual molecular mechanism in transcription, i.e. in the reading of the DNA sections relevant to the muscle fibres and their transfer into the corresponding blueprint. In the case of sorafenib, the researchers have uncovered an unusual molecular mechanism in transcription, i.e. in the reading of the DNA sections relevant to the muscle fibres and their transfer into the corresponding blueprint.This leads to impaired development of the skeletal muscle fibres.
Basis for therapeutic fine-tuning
The researchers also investigated the drugs nilotinib and imatinib, which belong to the same class of chemotherapeutic agents. Nilotinib is used in particular for chronic lymphocytic leukaemia (CLL), while imatinib is used to treat acute lymphoblastic leukaemia (ALL) and gastrointestinal stromal tumours (GIST). ‘Interestingly, these two tyrosine kinase inhibitors did not show a similar effect on muscle cell function,’ says PD Dr Nayak. According to the cell biologist, the critical evaluation of cancer-specific chemotherapeutic agents with regard to their effects on muscle physiology is the key to developing better therapies. ‘The detailed findings from our study provide the background and framework for similar future investigations to fine-tune chemotherapeutic treatment. The correct selection of drugs with minimal side effects or potentially harmful effects that can be counteracted is only possible with knowledge of the underlying affected signalling pathways.
Therefore, the implications of these findings for the development of balanced combination therapies for affected individuals to improve treatment are of immediate importance. Nevertheless, sorafenib is currently one of the best therapeutics for the treatment of HCC and RCC. ‘However, our findings have the potential to develop new therapeutic regimens to minimise chemotherapy-induced cachexia,’ says PD Dr Nayak.
SERVICE:
The original paper ‘Sorafenib induces cachexia by impeding transcriptional signalling of the SET1/MLL complex on muscle-specific genes’ can be found here:
https://www.cell.com/iscience/fulltext/S2589-0042(24)02138-2
For further information, please contact Dr Arnab Nayak, nayak.arnab@mh-hannover.de.
Chemotherapy fights cancer, but can also damage the muscles.
Copyright: Karin Kaiser/MHH
Researching muscle atrophy caused by chemotherapy: PD Dr Arnab Nayak.
Copyright: Karin Kaiser/MHH
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