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A kiss of death for cells

Prof. Dr. Peter Krammer of the German Cancer Research Centre has considerably contributed to clarifying the apoptotic signalling pathways in both normal and malignant cells. In addition, he has developed new therapeutic strategies for the treatment of those diseases that are the result of defective apoptosis regulation.

Prof. Dr. Peter Krammer © German Cancer Research Centre

It is a great pleasure to listen to Prof. Peter Krammer's lectures about programmed cell death. It is like listening to a criminal story when Krammer is talking about the "suicide of cells", about the "kiss of death" given to a cell when CD95L (the "death ligand") binds to its receptor. Krammer is also an expert in explaining the highly complex apoptosis signalling pathways in a way that is both fascinating and easy to understand.

Apoptosis vs. necrosis

The term "apoptosis" refers to the highly regulated process that allows cells to self-degrade. It is different from "necrosis", which refers to a passive type of cellular death. The use of the term "apoptosis" to describe programmed cell death goes back to a paper published by Kerr et al. ("Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics", Br. J. Cancer 26, 239 ff., 1972). However, 2,400 years ago, Hippocrates of Kos used the word to describe gangrene tissue that remained in the bandages that were used to treat injuries, hence exactly describing a physiological type of cell death (the Greek word "apoptosis" means the leaves falling from plants or trees in the autumn).

 

Artistic presentation of an apoptotic cell – painted by the Yale University student, Alex Marzuka, who sold the picture in an auction for the benefit of bone marrow donations. © theyaledoc.files.wordpress.com

While necrotic processes can lead cells to burst and lysosomal enzymes to be released, thereby triggering inflammation, apoptotic cells are removed with a specific and regulated programme that can prevent an inflammatory response: the cell membrane is retained and the cell volume is reduced in processes leading to numerous morphological changes; the cytoskeleton breaks up, causing the membrane to bulge outward. These bulges may eventually separate from the cell, taking some cytoplasm with them. These so-called apoptotic bodies are recognised by phagocytes, ingested and degraded. Before this happens, the chromatin is condensed, DNA degraded and the cell nucleus fragmented. The biochemical processes during apoptosis include the activation of endonucleases and the activation of cysteine proteinases, which are also referred to as caspases.

Apoptosis plays a key role in many developmental and pathological processes. During embryogenesis, those cells and tissues that are no longer needed are eliminated by apoptosis. A classical example of this is the webbing between the fingers and toes of human foetuses, which is apoptosed during the development of the individual digits, with the result that the digits are thereby separated. In adult organisms, millions of cells must also be eliminated every day, for example the erythrocytes or cells of the intestinal mucosa. However, errors in the complex apoptotic signalling pathways can result in severe diseases. While AIDS, stroke, Parkinson's and Alzheimer's diseases are characterised by excessive apoptotic activity, cancer and autoimmune diseases are characterised by an insufficient amount, in turn leading to uncontrolled cell proliferation.

Extrinsic and intrinsic signalling pathways

Apoptosis can be triggered in a cell either through the extrinsic pathway (death-receptor-mediated) or the intrinsic pathway (mediated through mitochondria), which are linked to each other. Krammer and his team at the German Cancer Research Centre (DKFZ) in Heidelberg have carried out important pioneering work in their research of these two signalling pathways. The researchers were able to show that the binding of the death ligand to the CD95 death receptor leads to the creation of a death-inducing signalling complex within just a few seconds of binding. This complex comprises several CD95 receptors, adapter proteins and caspases, which are activated proteolytically and trigger a caspase cascade in the cells.

Death-inducing signalling complex (DISC) © German Cancer Research Centre

This process leads to the activation of the so-called death caspases (for example, caspase 3), which cleave the "death substrates", which then lead to cell death. The intrinsic signalling pathway is initiated through a number of pro-apoptotic and anti-apoptotic proteins that are released from the mitochondria. The activation of this signalling pathway leads to the release of cytochrome c from the mitochondria, in turn resulting in the formation of a protein complex known as apoptosome. This leads to the activation of caspase 9, resulting in the activation of the caspase 3 and thereby triggering apoptosis.

Krammer was a member of the founding team of the biopharmaceutical company Apogenix (and now scientific advisor and member of the company's supervisory board), which develops innovative drugs that target apoptosis signalling pathways. Scientists in Krammer's laboratory succeeded in constructing a human fusion protein that captures the CD95L death ligand and blocks the extrinsic signalling pathway. Apogenix used this fusion protein to develop a drug that can be used for the treatment of diseases resulting from excessive apoptotic activity. The drug, which consists of the extracellular part of the CD95 receptor and an Fc antibody fragment, is currently being tested for its ability to prevent acute graft-versus-host disease (GVHD), which starts within the first three months after a transplant and is often fatal. A clinical phase I study was successfully completed in May 2009.

A selective anti-cancer substance from traditional Chinese medicine

Scutellaria baicalensis © Chinese Medicine News

On her search for plant substances that are able to trigger apoptosis, Dr. Min Li-Weber, a scientist in Prof. Krammer's laboratory, discovered a medicinal plant that is used in traditional Chinese medicine. This substance triggers apoptosis in leukaemia cells (malignant T-cells), but has very little effect on healthy T-lymphocytes. This substance is a flavonoid contained in the roots of a labiate (Baikal Skullcap, Scutellaria baicalensis, Chinese: huang qin). The researchers from Heidelberg have clarified the molecular mechanism of the action of the active ingredient wogonin (5,7-dihydroxy-8-methoxyflavon, Chinese: han huang qin su).

Chemical structure of wogonin © German Cancer Research Centre

In cancer cells, wogonin induces caspase-dependent apoptosis through the intrinsic mitochondrial signalling pathway in a dose-dependent manner. Wogonin leads to the release of larger quantities of hydrogen peroxide from complex I (NADH dehydrogenase) of the mitochondrial respiratory chain than in normal T-cells. The peroxide triggers a calcium response, which in turn initiates the apoptotic reaction cascade.

Preclinical experiments showed that wogonin treatment led to a drastic decrease of tumours in immunodeficient mice transplanted with a human leukaemia cell line (xenotransplant), without leading to toxic effects in the mice. These results are so promising that the researchers now envisage the development of wogonin into a drug for treating a range of leukaemias.

Prof. Dr. med. Peter Krammer  

Peter Krammer studied medicine and after graduation became a member of the group that was led by the well-known Danish immunologist Niels Jerne at the Basel Institute of Immunology (Jerne was awarded the Nobel Prize in Physiology and Medicine in 1984 for his theory on the natural selection of antibodies). Krammer then moved on to the Max Planck Institute of Immunobiology in Freiburg, where he worked for Prof. Otto Westphal and Prof. Klaus Eichmann, with whom he moved to the German Cancer Research Centre (DKFZ) in Heidelberg in 1976 to become the head of the Department of Immunogenetics. He has been the Acting Director of the Institute of Immunology and Genetics since 1990 and the spokesperson of the Tumour Immunology programme at the DKFZ since 1993. Krammer also spent some time as a visiting professor at the Department of Microbiology at the University of Texas, S. W. Medical School in Dallas, USA, and as a visiting researcher in the laboratory of the geneticist Prof. Albrecht Sippel, who is the founding director of the Centre of Molecular Biology in Heidelberg.

Krammer has been awarded numerous prizes for his groundbreaking research, which has been published in more than 376 scientific papers (listed in the NCBI's PubMed in July 2009), including the Robert Koch Prize, German Cancer Prize, Kitasato-Behring Prize, Avery Landsteiner Prize, Ernst Jung Prize and Lautenschläger Research Prize of the University of Heidelberg. In addition, he was also awarded the first prize of the International Cell Death Society and the Career Award of the European Cell Death Organisation (ECDO), which will organise its 17th Euroconference on Apoptosis from 23-26 September 2009 in Paris.

Further information:
Prof. Dr. med. Peter H. Krammer
Deutsches Krebsforschungszentrum Heidelberg/German Cancer Research Centre (DKFZ)
Tel.: +49 (0)6221-42 73 718
E-mail: p.krammer(at)dkfz.de
Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/a-kiss-of-death-for-cells