Radiation Toxicity: Apoptosis and\or Necrosis. Dmitri Popov. PhD, Radiobiology. MD (Russia) Advanced Medical Technology and Systems Inc. Canada. intervaccine@gmail.com

Radiation Toxicity: Apoptosis and\or Necrosis. Accumulating evidences suggest that induction of apoptosis alone is insufficient to account for the therapeutic effect of radiotherapy. Tumour Biol. 2010 Aug;31(4):363-72. doi: 10.1007/s13277-010-0042-8. Epub 2010 May 20. Radiation-induced cell death mechanisms. Eriksson D1, Stigbrand T.

Radiation Toxicity: Apoptosis and\or Necrosis. Moderate and high doses of radiation induces necrosis of radiosensitive cells with the subsequent formation of radiation toxins and their induced acute inflammatory processes. Radiation necrosis is the most substantial and most severe form of radiation induced injury, and when widespread, has grave therapeutic implications.

Radiation Toxicity: Apoptosis and\or Necrosis. Mild and Moderate doses and of radiation exposure induces apoptosis (controlled, programmed death of radiosensitive cells) without significant levels of specific radiation-induced toxin formation and without of inflammatory response.

Radiation Toxicity: Apoptosis and\or Necrosis. The type of Cell Death depend on doses of Radiation, Type of Radiation and Radiosensitivity of irradiated cells. Radiosensitivity of irradiated cells depend on mitotic rate, metabolic rate.

Radiation Toxicity: Apoptosis and\or Necrosis. Radiation induced Apoptosis and Necrosis as response of eukaryotic cells to influence of different types of radiation remain contraversion. Radiation induced cell death by triggering apoptosis pathways was described in many articles and supported by many scientists.

Radiation Toxicity: Apoptosis and\or Necrosis. However, some scientists and some institutions described processes developing in irradiated eukaryotic cells as necrosis and some scientists describing a variety of complex mechanism and mentioned that radiation-induced cell death could developing under different mechanisms of pathogenesis which include and apoptosis and necrosis.

Radiation Toxicity: Apoptosis and\or Necrosis. Activation of cysteine proteases, cleavage of PARP - poly (ADP-ribosyl) activation of nuclear proteins causes the inner mitochondrial membrane to become permeable for ions and other small molecules during both types of cell death- apoptosis and necrosis. Many mechanisms of cell necrosis and cell apoptosis are identical – for example, degradation of the Nuclear matrix is a Common Element during Radiation-Induced Apoptosis and Necrosis.

Radiation Toxicity: Apoptosis and\or Necrosis. During apoptosis, the activation of a family of cysteine proteases, or caspases, results in proteolytic cleavage of numerous substrates. Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme involved in DNA repair, is a well-known substrate for caspase-3 cleavage during apoptosis.

Radiation Toxicity: Apoptosis and\or Necrosis. Apoptotic death requires the controlled degradation of the cell. Proteases play a crucial role in this programmed cell death or apoptosis. However, proteases can play important role in development non-programmed cell death or necrosis. Possible, that cell apoptosis and cell necrosis share pathways for cell death up to some point of this pathways and after this point developing different mechanisms of death with different biological sequaele.

Radiation Toxicity: Apoptosis and\or Necrosis. Data from different sources described that the differences between apoptosis and necrosis are much less numerous than previously studies suggested. Joseph Dynlacht and his research group of scientists studied the outcome of human promyelocytic leukemia (HL60) cells irradiated with 10 or 50 Gy of X-rays and determined the mode of leukemic cell death. Different doses of X-rays induced different modes of cell death – cells irradiated with 10 Gy died by apoptosis; cells irradiated with 50Gy died predominantly by necrosis.

Radiation Toxicity: Apoptosis and\or Necrosis. The Cell Death Nomenclature Committee recommends the use of the appropriate diagnosis: Apoptotic Necrosis.

Radiation Toxicity: Apoptosis and\or Necrosis. Apoptosis is described as a normally active, programmed process of cell death devoid of inflammation and toxins.

Radiation Toxicity: Apoptosis and\or Necrosis. Necrosis possesses the characteristics of accidental or externally-induced cell death from the influence of different environmental factors and triggering development of inflammation and elaborating of toxins, release of proinflammatory active and toxic cellular contents into the intracellular and extracellular fluids and into the lymphatic systems and blood circulation

Radiation Toxicity: Apoptosis and\or Necrosis. Apoptosis : Inflammation never present. Toxic substances never present. Morphologically cells shrinks, become denser, condensation occur, original name – shrinkage necrosis. Mitochondria’s structure and functions are not affected. Karyorhexis – pyknotic nuclear fragments. DNA broken into segments. Caspase activation always present. Genetic control initiate apoptosis. The Budding phenomenon. Cell membrane not affected.

Radiation Toxicity: Apoptosis and\or Necrosis. Inflammation always present. Toxic substances always present. Morphologically cells swelling, lysis. Mitochondria’s structure and functions are affected.

Radiation Toxicity: Apoptosis and\or Necrosis. Karyolysis, Pyknosis, Karyorhesis. Nuclear swelling, Chromatin granular, Chromatin flocculation, Types of radiation induced damage of DNA: Breaks of the strand, alteration to bases, destruction of sugar, cross-links and formation of dimmers.

Radiation Toxicity: Apoptosis and\or Necrosis. Caspase depended initiation of developing of necrosis possible. Caspase-8 initiation possible with apoptosis and necrosis.

Radiation Toxicity: Apoptosis and\or Necrosis. Apoptosis can be induced through the activation of death receptors including Fas, TNFαR, DR3, DR4, and DR5 by their respective ligands. Death receptor ligands characteristically initiate signaling via receptor oligomerization, which in turn results in the recruitment of specialized adaptor proteins and activation of caspase cascades - See more at: http://www.cellsignal.com/contents/science-pathway-research-apoptosis/death-receptor-signaling-pathway/pathways-apoptosis-deathю .

Radiation Toxicity: Apoptosis and\or Necrosis. Activated caspase-8 stimulates apoptosis via two parallel cascades: it can directly cleave and activate caspase-3, or alternatively, it can cleave Bid, a pro-apoptotic Bcl-2 family protein. Truncated Bid (tBid) translocates to mitochondria, inducing cytochrome c release, which sequentially activates caspase-9 and -3. TNF-α and DR-3L can deliver pro- or antiapoptotic signals - See more at: http://www.cellsignal.com/contents/science-pathway-research-apoptosis/death-receptor-signaling-pathway/pathways-apoptosis-death .

Radiation Toxicity: Apoptosis and\or Necrosis. TNFαR and DR3 promote apoptosis via the adaptor proteins TRADD/ FADD and the activation of caspase-8. Interaction of TNF-α with TNFαR may activate the NF-κB pathway via NIK/IKK. The activation of NF-κB induces the expression of pro-survival genes including Bcl-2 and FLIP, the latter can directly inhibit the activation of caspase-8. - See more at: http://www.cellsignal.com/contents/science-pathway-research-apoptosis/death-receptor-signaling-pathway/pathways-apoptosis-death

Radiation Toxicity: Apoptosis and\or Necrosis. In the absence of caspase activation, stimulation of death receptors can lead to the activation of an alternative programmed cell death pathway termed necroptosis by forming complex IIb. - See more at: http://www.cellsignal.com/contents/science-pathway-research-apoptosis/death-receptor-signaling-pathway/pathways-apoptosis-death#sthash.gORBJNss.dpuf

Radiation Toxicity: Apoptosis and\or Necrosis. Apoptosis and necroptosis are distinct types of regulated cell death.

Radiation Toxicity: Apoptosis and\or Necrosis. Apoptosis is characterized by condensed cytosol, marginalized chromatin and nuclear fragmentation. Apoptosis requires caspases for its execution. This cell death pathway can be induced by caspase activation downstream of growth factor deprivation, DNA damage or ligands of the death receptor family, such as tumour necrosis factor (TNF), FAS and TNF-related apoptosis-inducing ligand (TRAIL). http://www.nature.com/nrm/journal/v14/n11/box/nrm3683_BX1.html

Radiation Toxicity: Apoptosis and\or Necrosis. Necroptosis is characterized by early plasma membrane permeabilization, translucent cytosol and swollen mitochondria. Necroptotic cells can be observed when cells are stimulated by pro-death signals, such as ligands of the death receptor family (including TNF, FAS or TRAIL), in the absence of caspase activation or in vivo after ischaemic injuries. http://www.nature.com/nrm/journal/v14/n11/box/nrm3683_BX1.html

Radiation Toxicity: Apoptosis and\or Necrosis. Receptor-interacting protein 1 (RIP1) kinase is required to mediate necroptosis signalling through the activation of RIP3, a downstream mediator of necroptosis. http://www.nature.com/nrm/journal/v14/n11/box/nrm3683_BX1.html http://www.intechopen.com/books/current-topics-in-ionizing-radiation-research/radiation-toxins-molecular-mechanisms-of-toxicity-and-radiomimetic-properties-

Radiation Toxicity: Apoptosis and\or Necrosis. Necrostatin 1 was isolated in a cell-based high-throughput chemical screen for inhibitors of caspase-independent necrosis6. Although the original necrostatin 1 isolated from the screen, methyl-thiohydantoin-Trp (MTH-Trp), can inhibit indoleamine 2,3-dioxygenase (IDO) activity as well as receptor-interacting protein 1 (RIP1) activity, an improved analogue of necrostatin 1, 7-Cl-O-Nec-1 (5-(7-chloro-1H- indol-3-yl)methyl)-3-methylimidazolidine-2,4-dione), has no IDO inhibitory activity. http://www.nature.com/nrm/journal/v14/n11/box/nrm3683_BX1.html

Radiation Toxicity: Apoptosis and\or Necrosis. 7-Cl-O-Nec-1 demonstrates exclusive selectivity towards RIP1, as it inhibits RIP1 kinase 1,000 times more potently than 485 other human kinases, including several other members of the RIP family, and it binds to RIP1 with high affinity (with a dissociation constant (Kd) of ~3 nM)3. 7-Cl-O-Nec-1 also targets RIP1 kinase specifically in vivo, as its ability to inhibit cell death is entirely dependent on the expression of RIP1. Degterev, A. et al. Identification of RIP1 kinase as a specific cellular target of necrostatins.Nature Chem. Biol. 4, 313–321 (2008).  Demonstrates that RIP1 kinase is the target of necrostatin 1.

Radiation Toxicity: Apoptosis and\or Necrosis. At the present time post radiation necroptosis can be considered as an alternative form of programmed cell death whose activation induces important biological consequences including immune reactions and induced inflammation. Post Radiation Apoptosis vs Post Radiation Necroptosis.