Cell death beyond apoptosis

Abstract

Though the term apoptosis was originated in pathology and developmental biology as an alternative to necrosis, the tissue necrosis with inflammation is irrelevant to cell culture conditions where apoptosis is mostly studied. Furthermore, no one single morphological feature is either necessary or sufficient to define apoptosis. The emerging biochemical definition, a cell death with caspase activation, allows the distinction of alternative forms of cell death. Thus, inhibition of caspases delays but does not prevent cell death. Slow cell death without caspase activation may nevertheless be associated with DNA fragmentation. Oncogenic Ras, Raf, and mitogen-activated kinases inhibit apoptosis by affecting the cytochrome C/caspase-9 pathway but may arrest growth and cause slow cell death with delayed DNA fragmentation. Such 'slow' cell death without caspase activation is often caused by chemotherapeutic drugs. Whether a cell will undergo apoptosis or slow death depends not only on a chemotherapeutic agent but also on the readiness of cellular caspases. Therefore, one can distinguish apoptosisprone (eg leukemia) vs apoptosis-resistant cells. Cell susceptibilities to spontaneous, starvation-induced and drug-induced apoptosis are correlated and characterize an apoptosis-prone phenotype. Finally, distinction of slow cell death allows rephrasing of a question regarding the goal of cancer therapy: apoptosis vs slow cell death, or cancer cell-selectivity regardless of the mode of cell death. Leukemia (2000) 14, 1502-1508.

Mitotic Arrest and Cell Fate: Why and How Mitotic Inhibition of Transcription Drives Mutually Exclusive Events

“…20 On a biochemical level, however, apoptosis can be defined as cell death mediated or accelerated by caspases. 21,22 Generally, cells could be either apoptosis-prone (with 'ready-to-go caspase cascades') or apoptosis-reluctant. [23][24][25][26] For example, leukemia cell lines such as Jurkat, HL60 and U937 readily undergo apoptosis.…”

The kiss of death: promises and failures of death receptors and ligands in cancer therapy

“…79 There are also reports that death receptors cannot only induce apoptosis but, in addition, necrotic cell death [80][81][82] which might be as important as the induction of apoptosis, especially with regard to cancer therapy. 83 Experiments with cells from Apaf-1 and caspase-3 knockout mice revealed the existence of two distinct pathways leading to nuclear apoptosis. 84 One caspasedependent pathway targets caspase-activated DNase (CAD), while another pathway is caspase-independent and mediated by the mitochondrial apoptosis-inducing factor (AIF).…”

In vitro susceptibility to TRAIL-induced apoptosis of acute leukemia cells in the context of TRAIL receptor gene expression and constitutive NF-κB activity

“…35,36 The extent of cell death was quantified as percentage of annexinV +ve cells, thus detecting both caspase-mediated apoptotic cell death as well as a possible distinct caspaseindependent mode of cell death. 37 Specific TRAIL-induced cell death was assumed, if the percentage of annexinV +ve cells/sample in the presence of TRAIL was at least 10% higher compared to the percentage of annexin V +ve cells/sample in the medium control.…”