A cells agony of choice : how to cross the Styx?

Das „Apoptose-Nekrose-Konzept“ wurde auf Basis distinkter Morphologien toter Zellen sowie der (patho)physiologischen Bedingungen ihres Auftretens begründet: (1) Apoptose, Kondensation/Fragmentation von Kern und Zytoplasma prominent, Ausschluss von Autolyse; koordinierte Selbstzerstörung der Zelle; (2) Nekrose, Zelllyse prominent; verursacht durch Zusammenbruch der Zellhomöostase nach massiver Zellschädigung. Dieser Vorschlag hatte eine kontroverse Debatte zur Folge und bald wurde deutlich, dass diese „Apoptose-Nekrose-Dichotomie“ nicht generell anwendbar war. Heutzutage ist allgemein anerkannt, dass Zellen mit unterschiedlichen Selbstzerstörungsprogrammen ausgestattet sind; dadurch wird eine flexible Reaktion einer Zelle auf physiologische oder pathologische Signale ermöglicht. Der vorliegende Artikel erinnert an die elektronenmikroskopischen und zytochemischen Untersuchungen von Adi Ellinger an kultivierten humanen Brustkrebszellen. Hiermit leistete er einen wesentlichen Beitrag zu der Erkenntnis, dass, unter bestimmten biologischen Bedingungen, die Autophagie ein Element des regulierten Zelltods ist; damit verbunden die Infragestellung der in den 1990er-Jahren noch vorherrschenden Einteilung von Zelltodkategorien als „Apoptose-Nekrose-Dichotomie“The original “apoptosisnecrosis” concept was based on morphology and (patho)physiological conditions of the occurrence of cell death: (1) apoptosis, with nuclear and cytoplasmic condensation/fragmentation prominent, exclusion of autolysis, considered to result from coordinated self-destruction of a cell; (2) necrosis, with cell lysis prominent, caused by violent environmental perturbation leading to collapse of internal homeostasis. This suggestion initiated a controversial discussion within the scientific community and it soon became clear that the “apoptosisnecrosis dichotomy” was not generally applicable. Nowadays, there is sufficient evidence that cells may activate diverse suicide pathways, thereby allowing a flexible response to environmental changes, either physiological or pathological. The present paper commemorates electron microscopic and cytochemical studies on cell death of cultured human mammary carcinoma cells performed by Adi Ellinger, adding a significant contribution to recognize that autophagy can be involved in regulated cell death, thereby challenging the apoptosisnecrosis dichotomy still predominant in the 1990s.(VLID)359171

Correction: 2-Deprenyl-Rheediaxanthone B Isolated from Metaxya rostrata Induces Active Cell Death in Colorectal Tumor Cells

Metaxya rostrata C. Presl (Metaxyaceae) is a common tree fern in Central and South America that is used for the treatment of intestinal ulcers and tumours in ethnic medicine. Using a bioactivity-guided strategy 2-deprenyl-rheediaxanthone B (XB) has been isolated as one of the active principles in this plant. XB induced loss of cell viability in colorectal cancer cell lines at IC(50) concentrations of 11–23 µM. This was caused by both accumulation of cells in the G2- and S-phase as well as by induction of active cell death in a time and concentration-dependent manner. Cells exposed to XB were incapable of undergoing regular mitosis due to down-regulation of FoxM1 and absence of chromosome condensation. The apoptosis-related proteins Bcl(2) and Bcl(xl) were up-regulated so that Caspase 3 was not activated and classical apoptosis was not observed. However, XB triggered damage pathways down-stream of ATR and activated Caspase 2 causing cell death by a mechanism similar to mitotic catastrophe. Our observations are the first to show the cytotoxic activity of 2-deprenyl-rheediaxanthone B and indicate that XB is an interesting new lead compound for cancer therapy that merits further development

XB-induced cell loss.

<p>Semiconfluent cell cultures of HCT116, DLD1, CaCo2, SW620, SW480 (<b>A</b>) and F331 and LT97 (<b>B</b>) were exposed to increasing concentrations of XB diluted into serum-free treatment medium. Viability was determined 48 hours later by MMT assay. The results shown are the mean±SD pooled from three independent experiments performed in triplicates. *, ** and *** indicate a significant difference as compared to control at p≤0.05, 0.01 and 0.001, respectively.</p

XB-induced active cell death.

<p><b>A, B, C, D</b>: In a parallel experiment cultures were fixed after 48 hours of XB-exposure and stained with Hoechst 33258 for visualisation of nuclear morphology (<b>A</b>: control SW480, <b>B</b>: XB treated SW480, <b>C</b>: control CaCo2, <b>D</b>: XB treated CaCo2). <b>E</b>: Semi-confluent cultures of SW480 were exposed to the indicated concentrations of XB and harvested 48 and 72 hours later for determination of mitochondrial membrane potential (MMP). The results shown are the mean±SD pooled from three independent experiments.</p

XB does not induce classical apoptosis.

<p>Protein lysates were harvested 20 hours after exposure to 20 µM XB and levels of Bcl_xl, Bcl₂, activated Caspase 3, PARP and cleaved PARP (<b>A</b>) as well as pro Caspase 2 and activated Caspase 2 (<b>B</b>) were analysed by western blotting. The figure shows representative examples of two independent experiments.</p