| Mode |
Characteristics |
| Apoptosis |
• A genetically-regulated type of programmed cell death.
• Follows either the intrinsic (mitochondrial) DNA damage-mediated pathway or the extrinsic death-receptor pathway, both of which involve activation of caspases [5].
• Involves chromatin/nuclear condensation, non-random DNA degradation (“laddering”), and cell fragmentation generating apoptotic bodies.
• In vascular endothelial cells, IR damage to the cell membrane can activate acid sphingomyelinase which hydrolyzes sphingomyelin to ceramide, triggering apoptosis [6]. |
| Autophagy |
• A genetically-regulated stress response seen in some human cancer cell lines exposed to IR [7-10].
• Cells exit the cell cycle, develop cytoplasmic vacuoles that sequester organelles such as mitochondria and ribosomes, auto-digest proteins and damaged organelles and recycle amino and fatty acids.
• Pro-death (versus pro-survival) signals may require hyper-activation of the autophagy pathway [11].
• Pathway is negatively regulated by the mTOR (mammalian target of rapamycin) protein.
|
| Mitotic catastrophe |
• The failure of a cell with damaged DNA to undergo proper mitosis [12].
• Likely caused by aberrant chromosome segregation/cell fusion.
• Cells are typically enlarged with abnormal spindles, micronuclei and de-condensed chromatin; can lead to multinucleated/polyploid giant cells.
• May be a key contributor to the loss of clonogenic potential in tumor cells and solid tumors exposed to IR, especially those with mutant p53 [11-13].
• Mitotic catastrophe may not represent a mode of cell death but rather a process preceding cell death by necrosis, apoptosis, etc. [14].
|
| Necrosis |
• Historically regarded as an uncontrolled (i.e., not genetically regulated) form of cell death following high-dose IR exposures that involves swelling of the cell and mitochondria, disintegration of the cell organelles and membrane, protein denaturation/coagulation and random DNA degradation [15].
• A programmed/genetically-regulated type of necrosis, necroptosis, was recently identified [16].
• IR was reported to induce necroptosis in thyroid and adrenocortical carcinoma cell lines; this response exhibits some overlap with apoptosis [17].
|
| Therapy-induced cellular senescence |
• A genetically-regulated response to IR-induced DNA damage seen in many solid tumor-derived cell lines, especially those with wild type p53 [18] although p53-independent and mutant-p53-dependent mechanisms have been described.
• Cells are growth-arrested for extended periods but remain viable and metabolically active, are enlarged and flattened, develop polyploidy and express the marker “senescence-associated b-galactosidase”.
• Important molecular
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