Metalloporphyrins inactivate caspase-3 and -8.
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Metalloporphyrins inactivate caspase-3 and -8. / Blumenthal, Signe B; Kiemer, Alexandra K; Tiegs, Gisa; Seyfried, Stefan; Höltje, Monika; Brandt, Birte; Höltje, Hans-Dieter; Zahler, Stefan; Vollmar, Angelika M.
In: FASEB J, Vol. 19, No. 10, 10, 2005, p. 1272-1279.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Metalloporphyrins inactivate caspase-3 and -8.
AU - Blumenthal, Signe B
AU - Kiemer, Alexandra K
AU - Tiegs, Gisa
AU - Seyfried, Stefan
AU - Höltje, Monika
AU - Brandt, Birte
AU - Höltje, Hans-Dieter
AU - Zahler, Stefan
AU - Vollmar, Angelika M
PY - 2005
Y1 - 2005
N2 - Activation of caspases represents one of the earliest biochemical indicators for apoptotic cell death. Therefore, measurement of caspase activity is a widely used and generally accepted method to determine apoptosis in a wide range of in vivo and in vitro settings. Numerous publications characterize the role of the heme-catabolizing enzyme heme oxygenase-1 (HO-1) in regulating apoptotic processes. Different metalloporphyrins representing inducers and inhibitors of this enzyme are often used, followed by assessment of apoptotic cell death. In the present work, we found that caspase-3-like activity, as well as activity of caspase-8 measured in either Fas (CD95) ligand-treated Jurkat T-lymphocytes or by the use of recombinant caspase-3 or -8, was inhibited by different metalloporphyrins (cobalt(III) protoporphyrin IX, tin and zinc(II) protoporphyrin-IX). Moreover, employing the mouse model of Fas-induced liver apoptosis these properties of porphyrins could also be demonstrated in vivo. The metalloporphyrins were shown to inhibit caspase-3-mediated PARP cleavage. Molecular modeling studies demonstrated that porphyrins can occupy the active site of caspase-3 in an energetically favorable manner and in a binding mode similar to that of known inhibitors. The data shown here introduce metalloporphyrins as direct inhibitors of caspase activity. This finding points to the need for careful employment of metalloporphyrins as modulators of HO-1.
AB - Activation of caspases represents one of the earliest biochemical indicators for apoptotic cell death. Therefore, measurement of caspase activity is a widely used and generally accepted method to determine apoptosis in a wide range of in vivo and in vitro settings. Numerous publications characterize the role of the heme-catabolizing enzyme heme oxygenase-1 (HO-1) in regulating apoptotic processes. Different metalloporphyrins representing inducers and inhibitors of this enzyme are often used, followed by assessment of apoptotic cell death. In the present work, we found that caspase-3-like activity, as well as activity of caspase-8 measured in either Fas (CD95) ligand-treated Jurkat T-lymphocytes or by the use of recombinant caspase-3 or -8, was inhibited by different metalloporphyrins (cobalt(III) protoporphyrin IX, tin and zinc(II) protoporphyrin-IX). Moreover, employing the mouse model of Fas-induced liver apoptosis these properties of porphyrins could also be demonstrated in vivo. The metalloporphyrins were shown to inhibit caspase-3-mediated PARP cleavage. Molecular modeling studies demonstrated that porphyrins can occupy the active site of caspase-3 in an energetically favorable manner and in a binding mode similar to that of known inhibitors. The data shown here introduce metalloporphyrins as direct inhibitors of caspase activity. This finding points to the need for careful employment of metalloporphyrins as modulators of HO-1.
KW - Animals
KW - Humans
KW - Mice
KW - Mice, Inbred BALB C
KW - Apoptosis
KW - Models, Molecular
KW - Jurkat Cells
KW - Caspase 3
KW - Caspase 8
KW - Caspases/antagonists & inhibitors/chemistry/metabolism
KW - Enzyme Inhibitors/pharmacology
KW - Fas Ligand Protein
KW - Heme Oxygenase-1/physiology
KW - Membrane Glycoproteins/pharmacology
KW - Metalloporphyrins/pharmacology
KW - Poly(ADP-ribose) Polymerases/metabolism
KW - Tumor Necrosis Factors/pharmacology
KW - Animals
KW - Humans
KW - Mice
KW - Mice, Inbred BALB C
KW - Apoptosis
KW - Models, Molecular
KW - Jurkat Cells
KW - Caspase 3
KW - Caspase 8
KW - Caspases/antagonists & inhibitors/chemistry/metabolism
KW - Enzyme Inhibitors/pharmacology
KW - Fas Ligand Protein
KW - Heme Oxygenase-1/physiology
KW - Membrane Glycoproteins/pharmacology
KW - Metalloporphyrins/pharmacology
KW - Poly(ADP-ribose) Polymerases/metabolism
KW - Tumor Necrosis Factors/pharmacology
M3 - SCORING: Journal article
VL - 19
SP - 1272
EP - 1279
JO - FASEB J
JF - FASEB J
SN - 0892-6638
IS - 10
M1 - 10
ER -