Evidence that desferrioxamine cannot enter cells by passive diffusion

Lloyd, John; Cable, Hazel C.; Rice‐Evans, Catherine

doi:10.1016/0006-2952(91)90109-i

Cited by 157 publications

(94 citation statements)

References 10 publications

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“…The finding that exposure to two structurally unrelated metal chelators preserved lysosomal stability both under and after the steady-state oxidative stress, and prevented apoptosis as well, is consistent with our previous observations when H # O # was used in large bolus doses [3,4]. The protection by pre-exposure to desferrioxamine, which is taken up only by endocytosis and stored intralysosomally [21][22][23], confirms that lysosomal vul-…”

Section: Figure 5 Effects Of Desferrioxamine and 22h-dipyridyl On Lysupporting

confidence: 79%

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Apoptosis induced by exposure to a low steady-state concentration of H2O2 is a consequence of lysosomal rupture

Antunes

Cadenas

Brunk

2001

Biochemical Journal

188

138

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We have re-examined the lysosomal hypothesis of oxidative-stress-induced apoptosis using a new technique for exposing cells in culture to a low steady-state concentration of H2O2. This steady-state technique mimics the situation in vivo better than the bolus-administration method. A key aspect of H2O2-induced apoptosis is that the apoptosis is evident only after several hours, although cells may become committed within a few minutes of exposure to this particular reactive oxygen species. In the present work, we were able to show, for the first time, several correlative links between the triggering effect of H2O2 and the later onset of apoptosis: (i) a short (15min) exposure to H2O2 caused almost immediate, albeit limited, lysosomal rupture; (ii) early lysosomal damage, and later apoptosis, showed a similar dose-related response to H2O2; (iii) both events were inhibited by pre-treatment with iron chelators, including desferrioxamine. This compound is known to be taken up by endocytosis only and thus to become localized in the lysosomal compartment. After exposure to oxidative stress, when cells were again in standard culture conditions, a time-dependent continuous increase in lysosomal rupture was observed, resulting in a considerably lowered number of intact lysosomes in apoptotic cells, whereas non-apoptotic cells from the same batch of oxidative-stress-exposed cells showed mainly intact lysosomes. Taken together, our results reinforce earlier findings and strongly suggest that lysosomal rupture is an early upstream initiating event, and a consequence of intralysosomal iron-catalysed oxidative processes, when apoptosis is induced by oxidative stress.

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Section: Figure 5 Effects Of Desferrioxamine and 22h-dipyridyl On Lysupporting

confidence: 79%

“…Desferrioxamine is taken up into cells by endocytosis [21][22][23] and, consequently, binds lysosomal low-molecular-mass redoxactive transition metals. 2,2h-Dipyridyl is a lipophilic compound that transverses membranes freely [24] ; hence, a broader cellular range of effects may be expected with 2,2h-dipyridyl.…”

Section: Fenton Chemistry Lysosomes and Apoptosismentioning

confidence: 99%

Apoptosis induced by exposure to a low steady-state concentration of H2O2 is a consequence of lysosomal rupture

Antunes

Cadenas

Brunk

2001

Biochemical Journal

188

138

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“…By contrast, they are markedly attenuated by iron chelators such as deferiprone or apoferritin, both more effective than desferrioxamine that does not readily cross the plasma membrane but is taken up by endocytosis. 40 Iron availability thus appears critical in influencing HTC death, strongly supporting the notion that it plays a central role in TNF and CHX toxicity. Low-mass iron is physiologically available in lysosomes, mainly deriving from the breakdown of autophagocytosed ferruginous materials, 25,41 such as ferritin and mitochondria that carry the major share of intracellular iron.…”

Section: Discussionmentioning

confidence: 66%

Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

et al. 2015

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, tandem fluorescent microtubule-associated protein 1 light chain 3 A/B (green/red fluorescent proteins chimera); TNFRSF1A/TNFR1, tumor necrosis factor receptor superfamily member 1A; TNFRSF1B/TNFR2, tumor necrosis factor receptor superfamily member 1B.Lysosomal membrane permeabilization (LMP) induced by oxidative stress has recently emerged as a prominent mechanism behind TNF cytotoxicity. This pathway relies on diffusion of hydrogen peroxide into lysosomes containing redox-active iron, accumulated by breakdown of iron-containing proteins and subcellular organelles. Upon oxidative lysosomal damage, LMP allows relocation to the cytoplasm of low mass iron and acidic hydrolases that contribute to DNA and mitochondrial damage, resulting in death by apoptosis or necrosis. Here we investigate the role of lysosomes and free iron in death of HTC cells, a rat hepatoma line, exposed to TNF following metallothionein (MT) upregulation. Iron-binding MT does not normally occur in HTC cells in significant amounts. Intracellular iron chelation attenuates TNF and cycloheximide (CHX)-induced LMP and cell death, demonstrating the critical role of this transition metal in mediating cytokine lethality. MT upregulation, combined with starvation-activated MT autophagy almost completely suppresses TNF and CHX toxicity, while impairment of both autophagy and MT upregulation by silencing of Atg7, and Mt1a and/or Mt2a, respectively, abrogates protection. Interestingly, MT upregulation by itself has little effect, while stimulated autophagy alone depresses cytokine toxicity to some degree. These results provide evidence that intralysosomal iron-catalyzed redox reactions play a key role in TNF and CHX-induced LMP and toxicity. The finding that chelation of intralysosomal iron achieved by autophagic delivery of MT, and to some degree probably of other ironbinding proteins as well, into the lysosomal compartment is highly protective provides a putative mechanism to explain autophagy-related suppression of death by TNF and CHX.

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“…2, B and C, and 4, B and C). Because of the poor membrane permeability of DFO, the chelator is probably taken up by fluid phase pinocytosis (81) and then incorporated into lysosomes during the endosomallysosomal maturation process (81)(82)(83). DFO has been reported to act as a weak base possessing lysosomotropic properties (84) that then alters the pH of the lysosomal compartment and decreases Cat D activity (85).…”

Section: Discussionmentioning

confidence: 99%

The Anticancer Agent Di-2-pyridylketone 4,4-Dimethyl-3-thiosemicarbazone (Dp44mT) Overcomes Prosurvival Autophagy by Two Mechanisms

Gutierrez¹,

Richardson²,

Jansson³

2014

Journal of Biological Chemistry

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Background: Autophagy is a prosurvival mechanism contributing to resistance against anticancer agents. Results: We demonstrate that the selective antitumor thiosemicarbazone di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) increases autophagosome synthesis but induces cell death by reducing autophagosome degradation. Conclusion: Dp44mT overcomes autophagy and utilizes the autophagic machinery to provoke cell death. Significance: These results indicate a new mechanism by which Dp44mT induces tumor cell death.

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Evidence that desferrioxamine cannot enter cells by passive diffusion

Cited by 157 publications

References 10 publications

Apoptosis induced by exposure to a low steady-state concentration of H2O2 is a consequence of lysosomal rupture

Apoptosis induced by exposure to a low steady-state concentration of H2O2 is a consequence of lysosomal rupture

Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

The Anticancer Agent Di-2-pyridylketone 4,4-Dimethyl-3-thiosemicarbazone (Dp44mT) Overcomes Prosurvival Autophagy by Two Mechanisms

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