Radiation Toxicity: Apoptosis and\or Necrosis.

$: Radiation Toxicity: Apoptosis and\or Necrosis.$
D M I T R I P O P O V P H D R A D I O B I O L O G Y M D ( R U S S I A )

A D V A N C E D M E D I C A L T E C H N O L O G Y A N D S Y S T E M S I N C C A N A D A

I N T E R V A C C I N E G M A I L C O M

Radiation Toxicity Apoptosis andor Necrosis


Accumulating evidences suggest that induction of apoptosis alone is insufficient to account for the therapeutic effect of radiotherapy

Tumour Biol 2010 Aug31(4)363-72 doi 101007s13277-010-0042-8 Epub 2010 May 20

Radiation-induced cell death mechanisms

Eriksson D1 Stigbrand T


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


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


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 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


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


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 ndash for example degradation of the Nuclear matrix is a Common

Element during Radiation-Induced Apoptosis and Necrosis


During apoptosis the activation of a family of cysteine proteases or caspases results in proteolyticcleavage 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


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


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 ndash cells irradiated with 10 Gy died by apoptosis cells irradiated with 50Gy died predominantly by necrosis


The Cell Death Nomenclature Committee recommends the use of the appropriate diagnosis

Apoptotic Necrosis


Apoptosis is described as a normally active programmed process of cell death devoid of

inflammation and toxins


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


Apoptosis Inflammation never present Toxic substances never present Morphologically cells shrinks become denser condensation occur original name ndash shrinkage necrosis Mitochondriarsquos

structure and functions are not affected Karyorhexisndash pyknotic nuclear fragments DNA broken into segments Caspase activation always present Genetic control initiate apoptosis The Budding phenomenon Cell membrane not affected


Necrosis

Inflammation always present

Toxic substances always present

Morphologically cells swelling lysis

Mitochondriarsquos structure and functions are

affected


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


Caspase depended initiation of developing

of necrosis possible Caspase-8 initiation

possible with apoptosis and 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 httpwwwcellsignalcomcontentsscience-pathway-research-apoptosisdeath-receptor-signaling-pathwaypathways-apoptosis-deathю


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 httpwwwcellsignalcomcontentsscience-pathway-research-apoptosisdeath-receptor-signaling-pathwaypathways-apoptosis-death


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 NIKIKK 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 httpwwwcellsignalcomcontentsscience-pathway-research-apoptosisdeath-receptor-signaling-pathwaypathways-apoptosis-death


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 httpwwwcellsignalcomcontentsscience-pathway-research-apoptosisdeath-receptor-signaling-pathwaypathways-apoptosis-deathsthashgORBJNssdpuf


Apoptosis and necroptosis are distinct types of regulated cell death


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 caspaseactivation 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)

httpwwwnaturecomnrmjournalv14n11boxnrm3683_BX1html


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



Receptor-interacting protein 1 (RIP1) kinase is required to mediate necroptosis signalling through the activation of RIP3 a downstream mediator of necroptosis


httpwwwintechopencombookscurrent-topics-in-ionizing-radiation-researchradiation-toxins-molecular-mechanisms-of-toxicity-and-radiomimetic-properties-


Necrostatin 1 was isolated in a cell-based high-throughput chemical screen for inhibitors of caspase-independent necrosis6 Although the original necrostatin1 isolated from the screen methyl-thiohydantoin-Trp(MTH-Trp) can inhibit indoleamine 23-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-24-dione) has no IDO inhibitory activity



7-Cl-O-Nec-1 demonstrates exclusive selectivity towards RIP1 as it inhibits RIP1 kinase 1000 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 kinasespecifically 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 necrostatinsNature Chem Biol 4 313ndash321 (2008)Demonstrates that RIP1 kinase is the target of necrostatin 1


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


Accumulating evidences suggest that induction of apoptosis alone is insufficient to account for the therapeutic effect of radiotherapy

Tumour Biol 2010 Aug31(4)363-72 doi 101007s13277-010-0042-8 Epub 2010 May 20

Radiation-induced cell death mechanisms

Eriksson D1 Stigbrand T































Apoptotic Necrosis













Necrosis





affected







































































Apoptotic Necrosis













Necrosis





affected





















































Necrosis





affected









































Radiation Toxicity: Apoptosis and\or Necrosis.

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Transcript of Radiation Toxicity: Apoptosis and\or Necrosis.