The Cytotoxicity of Tumor Necrosis Factor Depends on Induction of the Mitochondrial Permeability Transition

Pastorino, John G.; Simbula, Gabriella; Yamamoto, Kazuhiko; Glascott, Peter A.; Rothman, Ronald J.; Farber, John L.

doi:10.1074/jbc.271.47.29792

Cited by 258 publications

(175 citation statements)

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“…PK11195 facilitated mitochondrial permeability transition induced by a diversity of apoptosis inducers has been previously reported (Pastorino et al, 1994(Pastorino et al, , 1996Hirsch et al, 1998), as well as direct induction of ∆Ψ m dissipation in thymocytes (Tanimoto et al, 1999). The requirement for micromolar concentrations of PK11195 to achieve the effects described in this study suggests a mechanism of toxicity that is independent of the PBR, since the equilibrium-binding constant is only 1 nM (Le Fur et al, 1983).…”

Section: Discussionsupporting

confidence: 67%

“…Becker's group reported PK11195-induced mitochondrial proliferation using TEM in rat C6 glioma cells and pituitary GH 3 cells (Shiraishi et al, 1991;Black et al, 1994), however, the basis for this proliferation was not investigated. Transcription of nuclear mitochondrial biogenesis genes is induced by oxidative stress (Miranda et al, 1999), consistent with observations by us and by Camins et al (Camins et al, 1995a) that PK11195 induces ROS, and may therefore underlie the antioxidant reversible increase in JC-1 green and NAO fluorescence.PK11195 facilitated mitochondrial permeability transition induced by a diversity of apoptosis inducers has been previously reported (Pastorino et al, 1994(Pastorino et al, , 1996Hirsch et al, 1998), as well as direct induction of ∆Ψ m dissipation in thymocytes (Tanimoto et al, 1999). The requirement for micromolar concentrations of PK11195 to achieve the effects described in this study suggests a mechanism of toxicity that is independent of the PBR, since the equilibrium-binding constant is only 1 nM (Le Fur et al, 1983).…”

supporting

confidence: 67%

“…This ligand effects a diverse range of physiological actions including inhibition of cell proliferation and respiratory control (Hirsch et al, 1989;Camins et al, 1995b), effects on mitochondrial protein and cholesterol translocation Wright and Reichenbecher, 1999), induction of cell differentiation (Landau et al, 1998), heat shock protein expression (Camins et al, 1995a), and facilitation of a diverse range of apoptotic stimuli (Pastorino et al, 1996;Hirsch et al, 1998;Verma et al, 1998). Consequently, a clearly defined physiological role for the PBR has remained elusive.…”

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confidence: 99%

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Bcl-2 resistant mitochondrial toxicity mediated by the isoquinoline carboxamide PK11195 involves de novo generation of reactive oxygen species

et al. 2001

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SummaryResistance to apoptosis is a major obstacle preventing effective therapy for malignancy. Mitochondria localized anti-death proteins of the Bcl-2 family play a central role in inhibiting apoptosis and therefore present valid targets for novel therapy. The peripheral benzodiazepine receptor (PBR) shares a close physical association with the permeability transition pore complex (PTPC), a pivotal regulator of cell death located at mitochondrial contact sites. In this study we investigated the cytotoxicity of the PBR ligand, PK11195, in the micromolar concentration range. PK11195 induced antioxidant inhibitable collapse of the inner mitochondrial membrane potential (∆Ψ m ) and mitochondrial swelling in HL60 human leukaemia cells, but not in SUDHL4 lymphoma cells (which exhibited a higher level of reduced glutathione and relative tolerance to chemotherapy or pro-oxidant induced ∆Ψ m dissipation). PK11195 induced the production of hydrogen peroxide that was not inhibited by Bcl-2 transfection, nor depletion of mitochondrial DNA. ROS production was however blocked by protonophore, implicating a requirement for ∆Ψ m . Our findings suggest that PK11195-induced cytotoxicity relies upon Bcl-2 resistant generation of oxidative stress; a process only observed at concentrations several orders of magnitude higher that required to saturate its receptor. 1397-1404 © 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2001.1788, available online at http://www.idealibrary.com on http://www.bjcancer.com methyl-N-methyl-N-(1-methylpropyl)-isoquinoline carboxamide (PK11195), carbonylcyanide m-chlorophenylhdrazone (CCCP), propidium iodide and all cell culture reagents were purchased from Sigma-Aldrich Ltd, UK. FITC-conjugated mouse antihuman Bcl-2 monoclonal antibody, and the Dako intrastain fixation/permeabilization kit were purchased from Dako, UK. Cell culture and treatmentsHL60, KG1A, K652 cells stably transfected with the Bcl-2 gene (K562 B4) or vector only (K562 N2) (kindly provided by Dr DE Banker and Dr F Applebaum, The Fred Hutchinson Cancer Research Center, USA), and SUDHL4 lymphoma cell lines, were maintained in exponential suspension cultures in RPMI 1640 medium supplemented with 10% fetal calf serum, 5 mM glutamine, 100 µg ml -1 streptomycin and 100 U ml -1 penicillin. Cells were grown in a humidified atmosphere of 5% CO 2 /95% air at 37˚C. PK11195 was dissolved in ethanol at a stock concentration of 8.7 mg ml -1 , and added to cells at a 75 µM final concentration for 4 hours; vehicle alone was also used in medium. To test the effect of an antioxidant on PK11195 activity, cells were treated with 10 mM N-acetylcysteine for 45 minutes prior to treatment with PK11195.Cells were incubated with VP16, or ara-C at 10 µM final concentration for 24 hours, or with the thiol crosslinking prooxidant, diamide, at 100 µM concentration for 24 hours. The protonophore CCCP was used to dissipate ∆Ψ m by treating cells at a concentration of 10 µM for 15 minutes prior to treatment with PK11195. Depletion of mitochondrial DNAKG1A cells ...

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Section: Discussionsupporting

confidence: 67%

supporting

confidence: 67%

mentioning

confidence: 99%

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Bcl-2 resistant mitochondrial toxicity mediated by the isoquinoline carboxamide PK11195 involves de novo generation of reactive oxygen species

et al. 2001

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“…Since we did not have a direct method to detect MPT induction in intact cells, we utilized this method. Therefore, although several reports indicate the induction of MPT by TNF (Pastorino et al, 1996), we cannot distinguish MPT induction and the decrease in mitochondrial membrane potential, which is recently considered to be important for apoptosis signalings (Shimizu et al, 1998). Since PDTC can inhibit rotenone-induced apoptosis, cytochrome c release, and MPT induction, an antioxidantsensitive pathway might be involved between complex I inhibition and cytochrome c release or MPT induction in TNF signalings.…”

Section: Discussionmentioning

confidence: 81%

Inhibition of mitochondrial respiratory chain complex I by TNF results in cytochrome c release, membrane permeability transition, and apoptosis

1998

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“…This applies to apoptosis (Kroemer et al, , 1997b and at least to some cases of necrosis (Ankarcrona et al, 1995;Arora et al, 1997;Nieminen et al, 1995Nieminen et al, , 1996Nieminen et al, , 1997Packer et al, 1996;Pastorino et al, 1993Pastorino et al, , 1994Pastorino et al, , 1996Schinder et al, 1996;Snyder et al, 1992;Trost and Lemasters, 1996). Accordingly, pharmacological inhibition of PT by speci®c drugs acting on mitochondria can interfere with both apoptosis (Marchetti et al, 1996a;Zamzami et al, 1996) and necrosis (Ankarcrona et al, 1995;Arora et al, 1997;Nieminen et al, 1995Nieminen et al, , 1996Nieminen et al, , 1997Packer et al, 1996;Pastorino et al, 1993Pastorino et al, , 1994Pastorino et al, , 1996Schinder et al, 1996;Snyder et al, 1992;Trost and Lemasters, 1996). Similarly, hyperexpression of the Bcl-2 oncoprotein, which functions as an endogenous inhibitor of PT Zamzami et al, 1996), can prevent the induction of apoptosis (Cory, 1995;Reed, 1994;Yang and Korsmeyer, 1996) and, in some instances, that of necrosis (Kane et al, 1993;Martinou et al, 1994;Shimizu et al, 1995Shimizu et al, , 1996a.…”

Section: Introductionmentioning

confidence: 99%

The apoptosis-necrosis paradox. Apoptogenic proteases activated after mitochondrial permeability transition determine the mode of cell death

et al. 1997

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Mitochondrial alterations including permeability transition (PT) constitute critical events of the apoptotic cascade and are under the control of Bcl-2 related gene products. Here we show that induction of PT is su cient to activate CPP32-like proteases with DEVDase activity and the associated cleavage of the nuclear DEVDase substrate poly(ADP-ribose) polymerase (PARP). Thus, direct intervention on mitochondria using a ligand of the mitochondrial benzodiazepin receptor or a protonophore causes DEVDase activation. In addition, the DEVDase activation triggered by conventional apoptosis inducers (glucocorticoids or topoisomerase inhibitors) is prevented by inhibitors of PT. The protease inhibitor N-benzyloxycabonyl-Val-Ala-Asp-¯uoromethylketone (Z-VAD.fmk) completely prevents the activation of DEVDase and PARP cleavage, as well as the manifestation of nuclear apoptosis (chromatin condensation, DNA fragmentation, hypoploidy). In addition, Z-VAD.fmk delays the manifestation of apoptosis-associated changes in cellular redox potentials (hypergeneration of superoxide anion, oxidation of compounds of the inner mitochondrial membrane, depletion of non-oxidized glutathione), as well as the exposure of phosphatidylserine residues in the outer plasma membrane lea¯et. Although Z-VAD.fmk retards cytolysis, it is incapable of preventing disruption of the plasma membrane during protracted cell culture (12 ± 24 h), even in conditions in which it completely blocks nuclear apoptosis (chromatin condensation and DNA fragmentation). Electron microscopic analysis con®rms that cells treated with PT inducers alone undergo apoptosis, whereas cells kept in identical conditions in the presence of Z-VAD.fmk die from necrosis. These observations are compatible with the hypothesis that PT would be a rate limiting step in both the apoptotic and the necrotic modes of cell death. In contrast, it would be the availability of apoptogenic proteases that would determine the choice between the two death modalities.

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The Cytotoxicity of Tumor Necrosis Factor Depends on Induction of the Mitochondrial Permeability Transition

Cited by 258 publications

References 45 publications

Bcl-2 resistant mitochondrial toxicity mediated by the isoquinoline carboxamide PK11195 involves de novo generation of reactive oxygen species

Bcl-2 resistant mitochondrial toxicity mediated by the isoquinoline carboxamide PK11195 involves de novo generation of reactive oxygen species

Inhibition of mitochondrial respiratory chain complex I by TNF results in cytochrome c release, membrane permeability transition, and apoptosis

The apoptosis-necrosis paradox. Apoptogenic proteases activated after mitochondrial permeability transition determine the mode of cell death

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