Cationic Gradient Reversal and Cytoskeleton-independent Volume Regulatory Pathways Define an Early Stage of Apoptosis

Bortner, Carl D.; Sifre, Maria I.; Cidlowski, John A.

doi:10.1074/jbc.m707809200

Cited by 66 publications

(89 citation statements)

References 31 publications

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“…Cytoskeletal disruption inhibits the second stage of AVD and also apoptotic body formation. 7 As far as we know, these experimental manoeuvres do not exist in nature, but serve to unravel and support a connection between AVD and apoptotic body formation.…”

Section: Avd Is Required For Cell Dismantling Into Apoptotic Bodiesmentioning

confidence: 99%

“…More accurately, the electrolytic movements occurring early in the apoptotic process control both AVD and other downstream events. 6,7 Inhibition of K þ extrusion by increasing K þ extracellular concentration, or by means of K þ channel blockers, prevents all or the most relevant downstream events from taking place, including AVD and cytochrome c translocation. 28,29 The latter is inhibited even in cells stimulated for apoptosis with insults, whose mechanisms of action do not require caspases for cytochrome c release.…”

Section: The Apoptotic Network As An Integral Mechanism Of Controlmentioning

confidence: 99%

“…Two stages of AVD have been described, with distinct roles in the process of apoptosis. [5][6][7] The first stage is characterized by a reversal of the normal Na þ and K þ gradients, leading to Na þ accumulation and K þ extrusion. It is estimated that these electrolytic movements are responsible for 20-40% of the cell volume decrease, which occurs before cytochrome c release from the mitochondria.…”

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confidence: 99%

“…Different cytoskeleton-disrupting agents, such as cytochalasins B, D and E and latrunculin A, prevent this second round of volume loss, along with DNA degradation and formation of apoptotic bodies. 7,8 In this second stage, both cytochrome c release and caspases seem to be involved and required for AVD (reviewed in Remillard and Yuan 6 ). Yet, a channel-mediated K þ outward movement is activated by cytochrome c independently of initiator caspase-9 activation.…”

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Apoptotic volume decrease as a geometric determinant for cell dismantling into apoptotic bodies

et al. 2010

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Apoptosis is a mode of cell death through which cells are dismantled and cell remains are packed into small, membrane-bound, sealed vesicles called apoptotic bodies, which are easy to erase by phagocytosis by neighbouring and immune system cells. The end point of the process is to cleanly eliminate damaged or unnecessary cells without disrupting the surrounding tissue or eliciting an inflammatory response. The apoptotic process involves a series of specific events including deoxyribonucleic acid and nuclear fragmentation, protease-driven cleavage of specific substrates, which inhibits key survival functions and reorganizes the cell's structure, externalization of molecules involved in phagocytosis, membrane blebbing and cell shrinkage. Apoptotic volume decrease (AVD) leading to cell shrinkage is a core event in the course of apoptosis, the biological meaning of which has not been clearly ascertained. In this article we argue that volume loss is a geometrical requisite for cell dismantling into apoptotic bodies. This is derived from the cell's volume-to-surface ratio. Indeed, package of the original cell volume into smaller membrane-sealed vesicles requires that either cell membrane surface increase or cell volume decrease. In this sense, AVD provides a reservoir of membrane surface for apoptotic body formation. The strategic situation of AVD in the time course of apoptosis is also discussed in the context of apoptotic body formation.

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Section: Avd Is Required For Cell Dismantling Into Apoptotic Bodiesmentioning

confidence: 99%

Section: The Apoptotic Network As An Integral Mechanism Of Controlmentioning

confidence: 99%

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Apoptotic volume decrease as a geometric determinant for cell dismantling into apoptotic bodies

et al. 2010

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“…Apoptotic body formation and the loss of water bring about a decrease in total cell volume. Volume changes in apoptotic cells have been measured by various techniques, and shrinkage by as much as 40 -85% has been reported (11,16,34,53,76,90). Shrinkage due to dehydration has received the most attention in the literature and is sometimes referred to as "apoptotic volume decrease" (AVD).…”

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Possible causes of apoptotic volume decrease: an attempt at quantitative review

Model

2014

American Journal of Physiology-Cell Physiology

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Model MA. Possible causes of apoptotic volume decrease: an attempt at quantitative review. Am J Physiol Cell Physiol 306: C417-C424, 2014. First published November 6, 2013; doi:10.1152/ajpcell.00328.2013.-Cell shrinkage and dehydration are essential characteristics of apoptosis, and loss of as much as half of the initial cell volume is not uncommon. This phenomenon is usually explained by efflux of K ϩ and Cl Ϫ . We reexamine this hypothesis on the basis of the available data for ion concentrations and the requirements for osmotic equilibrium and electroneutrality. In addition to ion loss, we discuss the possible impacts of several other processes: efflux of low-molecular-weight osmolytes, acidification of the cytosol, effects of water channels and pumps, heterogeneity of intracellular water, and dissociation of apoptotic bodies. We conclude that most mammalian cells are theoretically capable of reducing their volume by 15-20% through ion loss or a decrease in cytosolic pH, although, in reality, the contribution of these mechanisms to apoptotic shrinkage may be smaller. Transitions between osmotically active and inactive water pools might influence cell volume as well; these mechanisms are poorly understood but are amenable to experimental study. Dissociation of apoptotic bodies is a separate mechanism of volume reduction and should be monitored closely; this can be best achieved by measurement of intracellular water, rather than cell volume. cell volume regulation; apoptosis; apoptotic volume decrease; intracellular water CELL SHRINKAGE is one the most reproducible signs of apoptosis (33,103). It has at least three distinct aspects: 1) weakening of the substrate attachment, resulting in cell rounding and reduced spreading, 2) dissociation of cell fragments known as apoptotic bodies, and 3) loss of intracellular water. Apoptotic body formation and the loss of water bring about a decrease in total cell volume. Volume changes in apoptotic cells have been measured by various techniques, and shrinkage by as much as 40 -85% has been reported (11,16,34,53,76,90). Shrinkage due to dehydration has received the most attention in the literature and is sometimes referred to as "apoptotic volume decrease" (AVD).The place of AVD in the sequence of apoptotic events and its significance for the rest of apoptosis have been addressed in numerous research papers and reviews (46,70,71,92,94). Apparently, AVD can be an early (5,8,15,28,34,49,53,81) or a late (26,60,85,90,117) response, depending on the particular system. A few exceptions to the rule that AVD must accompany apoptosis have also been described (11,13,56,65,121,127); nevertheless, it appears that, in the vast majority of apoptotic models, AVD does occur sooner or later.It has been hypothesized that the main purpose of AVD is to facilitate detachment of apoptotic bodies (91) or to oppose cell swelling and rupture that might develop otherwise (128). Although the definitive answer to this question is lacking, there can be little doubt that such a highly conserved property...

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Sphaeropsidin A C15–C16 Cross‐Metathesis Analogues with Potent Anticancer Activity

Wagh,

Berthold,

Majeed

et al. 2024

ChemMedChem

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We recently discovered that sphaeropsidin A (SphA), a fungal metabolite from Diplodia cupressi, overcomes apoptosis resistance in cancer cells by inducing cellular shrinkage by impairing regulatory volume increase. Previously, we prepared a pyrene‐conjugated derivative of SphA by a cross‐metathesis reaction involving the phytotoxin’s C15,C16‐alkene. This derivative’s evaluation in a cancer cell panel revealed a significant increase in potency, with the IC50 values 5–10× lower than those displayed by the original natural product. Herein, we describe the preparation and anticancer evaluation of fifteen novel C15,C16‐alkene cross‐metathesis analogues in which the pyrene moiety was replaced with other aromatic or non‐aromatic hydrophobic groups. The idea for this replacement was to prepare a family of compounds that would not be predicted to be mutagenic compared with the original pyrene analogue. We predict several of our new compounds to be non‐mutagenic, while retaining the high potency of the original pyrene‐containing analogues. Examples of these potential lead compounds included those containing pentamethylphenyl and triphenylethylene pendant groups. As an additional feature of the current investigation, we prepared several deuterated pyrene‐containing compounds to overcome intellectual property issues associated with non‐patentability of the original pyrene derivative.

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Cationic Gradient Reversal and Cytoskeleton-independent Volume Regulatory Pathways Define an Early Stage of Apoptosis

Cited by 66 publications

References 31 publications

Apoptotic volume decrease as a geometric determinant for cell dismantling into apoptotic bodies

Apoptotic volume decrease as a geometric determinant for cell dismantling into apoptotic bodies

Possible causes of apoptotic volume decrease: an attempt at quantitative review

Sphaeropsidin A C15–C16 Cross‐Metathesis Analogues with Potent Anticancer Activity

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