Regulated Necrotic Cell Death: New Approaches to Pharmacotherapy

In many diseases, tissue is damaged as a consequence of increased cell death, particularly via regulated necrotic cell death modalities. This process can be controlled by small molecules, as scientists of Helmholtz Zentrum München report in a recent review article in Nature Reviews Drug Discovery.

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Harmful influences such as toxins or a transient lack of oxygen in tissues may cause cell death, culminating in tissue inflammation. This inflammation in turn attracts macrophages, which secrete chemical messengers such as the tumor necrosis factor. Therefore, in addition to apoptosis, regulated necrotic cell death pathways are triggered in the area of the initial tissue damage. “This induced regulated cell death can be blocked pharmacologically,” Dr. Marcus Conrad and Dr. José Pedro Friedmann Angeli summarize now. Both scientists conduct research at the Institute of Developmental Genetics of Helmholtz Zentrum München. Depending on the type of tissue, necrotic lesions may regenerate completely for instance through regrowth of intestinal cells following a viral infection. In other cases, the body replaces necrotic tissue parts with connective tissue scarring, e.g. in the heart muscle after cardiac infarction, with corresponding functional impairment of the organ.

New approaches to therapy

“For a long time it was assumed that only apoptosis could be blocked with inhibitors in order to prevent degenerative diseases,” said Conrad. “Yet in recent years it has become evident that necrotic cell death also follows clearly defined routines which can be manipulated by small molecules.” Moreover, many diseases are not caused by an apoptotic process, but rather by regulated necrotic cell death. These processes can be modulated pharmacologically. They are considered potential targets for therapies in the area of degenerative diseases and cancer. “Based on these new findings, scientists in recent years have begun to develop novel, highly specific molecules,” Conrad added, “for example, necrostatin for necroptosis* or ferrostatin and liproxstatin for ferroptosis**. With the increasing understanding on how cell die sufficient knowledge has been gained paving the way  for the preclinical and clinical development of new drugs. In the future, Conrad expects to find ways to induce regulated necrotic cell death in cancer cells, which would lead to promising new approaches to treat cancer effectively.

Further information

Publication: Conrad, M. et al., “Regulated necrosis: disease relevance and therapeutic opportunities“. Nature Reviews, doi:10.1038/nrd.2015.6. Link to the original publication

* Necroptosis: Already in 2005 Junying Yuan coined the term necroptosis, a combination of the words apoptosis and necrosis (Nat Chem Biol 2005, 1(2):112-9). Necroptosis is characterized by the activation of death receptors similar to those in apoptosis, but executed by different downstream mechanisms.

**Ferroptosis: Ferroptosis is a newly identified form of regulated cell death and is involved in numerous disease-promoting processes.

As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,300 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members.

Rising life expectancy is causing an increase in age-related, but also sociological and environmental, influences on the genes. The Institute of Developmental Genetics (IDG) examines these changes in genetic material. In the Mouse Genetics group, genetic animal models are developed to investigate various diseases. These models are analyzed in the Disease Modelling research group in order to identify gene functions and cell processes and evaluate the influence of the environment and aging processes. The group focuses on the examination of neurological and psychiatric diseases.

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Regulated Necrotic Cell Death: New Approaches to Pharmacotherapy