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Significance of p53 dynamics in regulating apoptosis in response to ionizing radiation, and polypharmacological strategies.

Liu B, Bhatt D, Oltvai ZN, Greenberger JS, Bahar I - Sci Rep (2014)

Bottom Line: Here we build a stochastic model of p53 induced apoptosis comprised of coupled modules of nuclear p53 activation, mitochondrial cytochrome c release and cytosolic caspase activation that also takes into account cellular heterogeneity.Our simulations show that the strength of p53 transcriptional activity and its coupling (or timing with respect) to mitochondrial pore opening are major determinants of cell fate: for systems where apoptosis is elicited via a p53-transcription-independent mechanism, direct activation of Bax by p53 becomes critical to IR-induced-damage initiation.In contrast, the combined inhibition of Bid and Bax elicits an anti-apoptotic response that is effective over a range of time delays.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Computational &Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA [2].

ABSTRACT
Developing pharmacological strategies for controlling ionizing radiation (IR)-induced cell death is important for both mitigating radiation damage and alleviating the side effects of anti-cancer radiotherapy manifested in surrounding tissue morbidity. Exposure to IR often triggers the onset of p53-dependent apoptotic pathways. Here we build a stochastic model of p53 induced apoptosis comprised of coupled modules of nuclear p53 activation, mitochondrial cytochrome c release and cytosolic caspase activation that also takes into account cellular heterogeneity. Our simulations show that the strength of p53 transcriptional activity and its coupling (or timing with respect) to mitochondrial pore opening are major determinants of cell fate: for systems where apoptosis is elicited via a p53-transcription-independent mechanism, direct activation of Bax by p53 becomes critical to IR-induced-damage initiation. We further show that immediate administration of PUMA inhibitors following IR exposure effectively suppresses excessive cell death, provided that there is a strong caspase/Bid feedback loop; however, the efficacy of the treatment diminishes with increasing delay in treatment implementation. In contrast, the combined inhibition of Bid and Bax elicits an anti-apoptotic response that is effective over a range of time delays.

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Potential mitigation of radiation damage via individual and combination therapies.Panels (A) and (B) show the effects of therapies based on single targets, PUMA, Bid, caspase-3, Bax, or their combination when inhibitors are administered at 15 min (A) and 12 h (B) after radiation exposure. Bid and Bax appear to be the most effective targets even when inhibited with a time delay. The control (no inhibition) is shown in both panels. The efficacy of PUMA inhibition strongly depends on the timing of the drug treatment. (C) Time evolution of caspase-3 in the absence of inhibitors (black) and in the presence inhibitors of PUMA and C3 (pink), and PUMA and Bax (blue). (D) A reduction in caspase/tBid feedback strength (k28) (from 0.5 to 0.3 μM−1s−1) rescues the efficacy of PUMA inhibitor administrated after a delay of 12 h.
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f7: Potential mitigation of radiation damage via individual and combination therapies.Panels (A) and (B) show the effects of therapies based on single targets, PUMA, Bid, caspase-3, Bax, or their combination when inhibitors are administered at 15 min (A) and 12 h (B) after radiation exposure. Bid and Bax appear to be the most effective targets even when inhibited with a time delay. The control (no inhibition) is shown in both panels. The efficacy of PUMA inhibition strongly depends on the timing of the drug treatment. (C) Time evolution of caspase-3 in the absence of inhibitors (black) and in the presence inhibitors of PUMA and C3 (pink), and PUMA and Bax (blue). (D) A reduction in caspase/tBid feedback strength (k28) (from 0.5 to 0.3 μM−1s−1) rescues the efficacy of PUMA inhibitor administrated after a delay of 12 h.

Mentions: Figure 7 illustrates the efficacy of simulated drug treatments administered at two different times after exposure to IR: immediately (with a time lag of 15 minutes succeeding IR exposure, Figure 7A) and after a delay of 12 hours (Figure 7B). The treatments involve administration of individual inhibitors for four targets, PUMA, Bid, caspase-3 and Bax, or combined therapies targeting pairs of these proteins. All (virtual) inhibitors are assumed to have nanomolar binding affinity to their target proteins. In the absence of treatment, the given radiation dose leads to sustained caspase-3 activity.


Significance of p53 dynamics in regulating apoptosis in response to ionizing radiation, and polypharmacological strategies.

Liu B, Bhatt D, Oltvai ZN, Greenberger JS, Bahar I - Sci Rep (2014)

Potential mitigation of radiation damage via individual and combination therapies.Panels (A) and (B) show the effects of therapies based on single targets, PUMA, Bid, caspase-3, Bax, or their combination when inhibitors are administered at 15 min (A) and 12 h (B) after radiation exposure. Bid and Bax appear to be the most effective targets even when inhibited with a time delay. The control (no inhibition) is shown in both panels. The efficacy of PUMA inhibition strongly depends on the timing of the drug treatment. (C) Time evolution of caspase-3 in the absence of inhibitors (black) and in the presence inhibitors of PUMA and C3 (pink), and PUMA and Bax (blue). (D) A reduction in caspase/tBid feedback strength (k28) (from 0.5 to 0.3 μM−1s−1) rescues the efficacy of PUMA inhibitor administrated after a delay of 12 h.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150106&req=5

f7: Potential mitigation of radiation damage via individual and combination therapies.Panels (A) and (B) show the effects of therapies based on single targets, PUMA, Bid, caspase-3, Bax, or their combination when inhibitors are administered at 15 min (A) and 12 h (B) after radiation exposure. Bid and Bax appear to be the most effective targets even when inhibited with a time delay. The control (no inhibition) is shown in both panels. The efficacy of PUMA inhibition strongly depends on the timing of the drug treatment. (C) Time evolution of caspase-3 in the absence of inhibitors (black) and in the presence inhibitors of PUMA and C3 (pink), and PUMA and Bax (blue). (D) A reduction in caspase/tBid feedback strength (k28) (from 0.5 to 0.3 μM−1s−1) rescues the efficacy of PUMA inhibitor administrated after a delay of 12 h.
Mentions: Figure 7 illustrates the efficacy of simulated drug treatments administered at two different times after exposure to IR: immediately (with a time lag of 15 minutes succeeding IR exposure, Figure 7A) and after a delay of 12 hours (Figure 7B). The treatments involve administration of individual inhibitors for four targets, PUMA, Bid, caspase-3 and Bax, or combined therapies targeting pairs of these proteins. All (virtual) inhibitors are assumed to have nanomolar binding affinity to their target proteins. In the absence of treatment, the given radiation dose leads to sustained caspase-3 activity.

Bottom Line: Here we build a stochastic model of p53 induced apoptosis comprised of coupled modules of nuclear p53 activation, mitochondrial cytochrome c release and cytosolic caspase activation that also takes into account cellular heterogeneity.Our simulations show that the strength of p53 transcriptional activity and its coupling (or timing with respect) to mitochondrial pore opening are major determinants of cell fate: for systems where apoptosis is elicited via a p53-transcription-independent mechanism, direct activation of Bax by p53 becomes critical to IR-induced-damage initiation.In contrast, the combined inhibition of Bid and Bax elicits an anti-apoptotic response that is effective over a range of time delays.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Computational &Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA [2].

ABSTRACT
Developing pharmacological strategies for controlling ionizing radiation (IR)-induced cell death is important for both mitigating radiation damage and alleviating the side effects of anti-cancer radiotherapy manifested in surrounding tissue morbidity. Exposure to IR often triggers the onset of p53-dependent apoptotic pathways. Here we build a stochastic model of p53 induced apoptosis comprised of coupled modules of nuclear p53 activation, mitochondrial cytochrome c release and cytosolic caspase activation that also takes into account cellular heterogeneity. Our simulations show that the strength of p53 transcriptional activity and its coupling (or timing with respect) to mitochondrial pore opening are major determinants of cell fate: for systems where apoptosis is elicited via a p53-transcription-independent mechanism, direct activation of Bax by p53 becomes critical to IR-induced-damage initiation. We further show that immediate administration of PUMA inhibitors following IR exposure effectively suppresses excessive cell death, provided that there is a strong caspase/Bid feedback loop; however, the efficacy of the treatment diminishes with increasing delay in treatment implementation. In contrast, the combined inhibition of Bid and Bax elicits an anti-apoptotic response that is effective over a range of time delays.

Show MeSH
Related in: MedlinePlus