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Temporal Heterogeneity Metrics in Apoptosis Induced by Anticancer Drugs.


ABSTRACT: The apoptotic process is highly heterogeneous and asynchronous. A long-standing question is how many parameters define the time and reversibility of the apoptotic response at a single-cell level. We characterized at the single-cell and population levels the time sequence of apoptotic events in response to anti-cancer drugs using extrinsic and intrinsic apoptotic stimuli. We show that the temporal sequence of major apoptotic events is the same in response to all anti-cancer drugs studied: the apoptotic volume decrease and Na+ influx occur rapidly and are tightly coordinated with mitochondrial outer membrane depolarization (MOMP), mitochondrial inner membrane depolarization and a decrease in the production of reactive oxygen species (ROS). Phosphatidylserine externalization usually starts after MOMP and precedes caspase 3/7 activation. Activation of caspases 3/7 is a slow process that always starts after MOMP, with significant delay. Cell-to-cell variability of the MOMP onset is described by Gaussian distribution, whereas the ?-distribution model describes cellular variability in the duration of MOMP-to-caspase activation stages. Cells from the pre-MOMP stage to the after-caspase 3/7 activation stage coexist for many hours. We demonstrated by FACS that cells in the pre-MOMP stage can recover after apoptotic stimuli, rarely recover after MOMP but before caspase 3/7 activation, and are unable to recover after caspase 3/7 activation. We propose a double-stroke model for apoptosis execution.

SUBMITTER: Vorobjev I 

PROVIDER: S-EPMC6728451 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Temporal Heterogeneity Metrics in Apoptosis Induced by Anticancer Drugs.

Vorobjev Ivan I   Barteneva Natasha S NS  

The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 20150402 7


The apoptotic process is highly heterogeneous and asynchronous. A long-standing question is how many parameters define the time and reversibility of the apoptotic response at a single-cell level. We characterized at the single-cell and population levels the time sequence of apoptotic events in response to anti-cancer drugs using extrinsic and intrinsic apoptotic stimuli. We show that the temporal sequence of major apoptotic events is the same in response to all anti-cancer drugs studied: the apo  ...[more]

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