Difference between revisions of "Soller 2007 Mol Pharmacol"
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|year=2007 | |year=2007 | ||
|journal=Molecular Pharmacology | |journal=Molecular Pharmacology | ||
|abstract=Thiazolidinediones are synthetic agonists for the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) | |abstract=Thiazolidinediones are synthetic agonists for the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) and are therapeutically used as insulin sensitizers. Besides therapeutical benefits, potential side effects such as the induction of cell death by thiazolidinediones deserve consideration. Although PPARγ-dependent and -independent cell death in response to thiazolidinediones has been described, we provide evidence supporting a new mechanism to account for thiazolidinedione-initiated but PPARγ-independent cell demise. In Jurkat T cells, ciglitazone and troglitazone provoked rapid and dose-dependent cell death, whereas rosiglitazone did not alter cell viability. We found induction of apoptosis by troglitazone, whereas ciglitazone caused necrosis. Because preincubation with the reactive oxygen species (ROS) scavengers manganese(III) tetrakis(4-benzoic acid) porphyrin and vitamin C significantly inhibited ciglitazone- and partially troglitazone-mediated cell death, we suggest that ROS contribute to cytotoxicity. Assuming that ROS originate from mitochondria, studies in submitochondrial particles demonstrated that all thiazolidinediones inhibited complex I of the mitochondrial respiratory chain. However, only ciglitazone and troglitazone lowered complex II activity as well. Pharmacological inhibition of complexes I and II documented that complex II inhibition in Jurkat cells caused massive apoptotic cell death, whereas inhibition of complex I provoked only marginally apoptosis after 4-h treatment. Therefore, inhibition of complex II by ciglitazone and troglitazone is the main trigger of cell death. ATP depletion by ciglitazone, in contrast to troglitazone, is responsible for induction of necrosis. Our results demonstrate that despite their similar molecular structure, thiazolidinediones differently affect cell death, which might help to explain some adverse effects occurring during thiazolidinedione-based therapies. | ||
and are therapeutically used as insulin sensitizers. Besides therapeutical benefits, potential side effects such as the induction | |||
of cell death by thiazolidinediones deserve consideration. Although PPARγ-dependent and -independent cell death in response to thiazolidinediones has been described, we provide evidence supporting a new mechanism to account for thiazolidinedione- | |||
initiated but PPARγ-independent cell demise. In Jurkat T cells, ciglitazone and troglitazone provoked rapid and dose-dependent cell death, whereas rosiglitazone did not alter cell viability. We found induction of apoptosis by troglitazone, whereas ciglitazone caused necrosis. Because preincubation with the reactive oxygen species (ROS) scavengers manganese(III) tetrakis(4-benzoic acid) porphyrin and vitamin C significantly inhibited ciglitazone- and partially troglitazone-mediated cell death, we suggest that ROS contribute to cytotoxicity. | |||
Assuming that ROS originate from mitochondria, studies in submitochondrial particles demonstrated that all thiazolidinediones | |||
inhibited complex I of the mitochondrial respiratory chain. However, only ciglitazone and troglitazone lowered complex II activity as well. Pharmacological inhibition of complexes I and II documented that complex II inhibition in Jurkat cells caused massive apoptotic cell death, whereas inhibition of complex I provoked only marginally apoptosis after 4-h treatment. Therefore, inhibition of complex II by ciglitazone and troglitazone is the main trigger of cell death. ATP depletion by ciglitazone, in contrast to troglitazone, is responsible for induction of necrosis. Our results demonstrate that despite their similar molecular structure, thiazolidinediones differently affect cell death, which might help to explain some adverse effects occurring during thiazolidinedione-based therapies. | |||
|info=[http://www.ncbi.nlm.nih.gov/pubmed/17325128 PMID: 17325128] | |info=[http://www.ncbi.nlm.nih.gov/pubmed/17325128 PMID: 17325128] | ||
}} | }} | ||
Revision as of 10:34, 24 September 2010
| Soller M, Dröse S, Brandt U, Brüne B, von Knethen A (2007) Mechanism of Thiazolidinedione-Dependent Cell Death in Jurkat T Cells. Mol Pharmacol. 71(6): 1535-4 |
Soller M, Droese S, Brandt U, Bruene B, von Knethen A (2007) Molecular Pharmacology
Abstract: Thiazolidinediones are synthetic agonists for the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) and are therapeutically used as insulin sensitizers. Besides therapeutical benefits, potential side effects such as the induction of cell death by thiazolidinediones deserve consideration. Although PPARγ-dependent and -independent cell death in response to thiazolidinediones has been described, we provide evidence supporting a new mechanism to account for thiazolidinedione-initiated but PPARγ-independent cell demise. In Jurkat T cells, ciglitazone and troglitazone provoked rapid and dose-dependent cell death, whereas rosiglitazone did not alter cell viability. We found induction of apoptosis by troglitazone, whereas ciglitazone caused necrosis. Because preincubation with the reactive oxygen species (ROS) scavengers manganese(III) tetrakis(4-benzoic acid) porphyrin and vitamin C significantly inhibited ciglitazone- and partially troglitazone-mediated cell death, we suggest that ROS contribute to cytotoxicity. Assuming that ROS originate from mitochondria, studies in submitochondrial particles demonstrated that all thiazolidinediones inhibited complex I of the mitochondrial respiratory chain. However, only ciglitazone and troglitazone lowered complex II activity as well. Pharmacological inhibition of complexes I and II documented that complex II inhibition in Jurkat cells caused massive apoptotic cell death, whereas inhibition of complex I provoked only marginally apoptosis after 4-h treatment. Therefore, inhibition of complex II by ciglitazone and troglitazone is the main trigger of cell death. ATP depletion by ciglitazone, in contrast to troglitazone, is responsible for induction of necrosis. Our results demonstrate that despite their similar molecular structure, thiazolidinediones differently affect cell death, which might help to explain some adverse effects occurring during thiazolidinedione-based therapies.
Labels:
Regulation: Respiration; OXPHOS; ETS Capacity"Respiration; OXPHOS; ETS Capacity" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property.
HRR: Oxygraph-2k
