Difference between revisions of "Opalka 2002 Biochem Pharmacol"
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{{Publication | {{Publication | ||
|title=Opalka JR, Gellerich FN, Kling L, Müller-Beckmann B, Zierz S (2002) Effect of the new matrix metalloproteinase inhibitor RO-28-2653 on mitochondrial function. Biochem Pharmacol 63: 725- | |title=Opalka JR, Gellerich FN, Kling L, Müller-Beckmann B, Zierz S (2002) Effect of the new matrix metalloproteinase inhibitor RO-28-2653 on mitochondrial function. Biochem Pharmacol 63:725-32. | ||
|info=[http://www.ncbi.nlm.nih.gov/pubmed/11992641 PMID:11992641] | |info=[http://www.ncbi.nlm.nih.gov/pubmed/11992641 PMID: 11992641] | ||
|authors=Opalka JR, Gellerich FN, Kling L, Mueller-Beckmann B, Zierz S | |authors=Opalka JR, Gellerich FN, Kling L, Mueller-Beckmann B, Zierz S | ||
|year=2002 | |year=2002 | ||
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|abstract=Matrix metalloproteinases (MMPs) have recently become interesting as potential anticancer drugs. RO-28-2653 is a promising compound because of its antimetastatic and antiangiogenic activities. Due to the structural similarity of RO-28-2653 to mitochondriotoxic agents, speculation has arisen that this substance might impair mitochondrial function. We, therefore, investigated the effects of RO-28-2653 on mitochondrial enzymes and on the functional properties of isolated mitochondria and skinned muscle fibers from rat hearts. Results were compared to the action of amytal and 2,4-dinitrophenol (2,4-DNP), both of which are well documented mitochondriotoxic compounds. In contrast to 2,4-DNP, RO-28-2653 did not uncouple oxidative phosphorylation, although higher concentrations of the compound did impair mitochondrial function. Using malate/pyruvate as substrate, 50 μM of RO-28-2653 inhibited mitochondrial respiration in isolated mitochondria and skinned fibers by 23 and 11%, respectively while 2 mM of amytal elicited almost complete inhibition of the mitochondrial respiration. RO-28-2653 (50 μM) inhibited succinate-dependent respiration in both systems by 43 and 24%, respectively while 2 mM of amytal caused 41 and 23% inhibition, respectively. There was no change in the ADP/O ratios. RO-28-2653 (50 μM) did not significantly alter the activity of the respiratory chain complexes or succinate dehydrogenase, although citrate synthase (CS) was inhibited by upto 71%. This inhibition was non-competitive at a Ki of 25±5 μM. Inhibitory effects in the presence of hydrophobic substances, such as BSA and Triton X-100, were significantly lower in both test systems. In conclusion, high concentrations of RO-28-2653 impair mitochondrial function, although compared to amytal and 2,4-DNP, this is rather low. The resultant impairment is less pronounced in the more complex skinned muscle fiber system, and is dependent on hydrophobic interactions. | |abstract=Matrix metalloproteinases (MMPs) have recently become interesting as potential anticancer drugs. RO-28-2653 is a promising compound because of its antimetastatic and antiangiogenic activities. Due to the structural similarity of RO-28-2653 to mitochondriotoxic agents, speculation has arisen that this substance might impair mitochondrial function. We, therefore, investigated the effects of RO-28-2653 on mitochondrial enzymes and on the functional properties of isolated mitochondria and skinned muscle fibers from rat hearts. Results were compared to the action of amytal and 2,4-dinitrophenol (2,4-DNP), both of which are well documented mitochondriotoxic compounds. In contrast to 2,4-DNP, RO-28-2653 did not uncouple oxidative phosphorylation, although higher concentrations of the compound did impair mitochondrial function. Using malate/pyruvate as substrate, 50 μM of RO-28-2653 inhibited mitochondrial respiration in isolated mitochondria and skinned fibers by 23 and 11%, respectively while 2 mM of amytal elicited almost complete inhibition of the mitochondrial respiration. RO-28-2653 (50 μM) inhibited succinate-dependent respiration in both systems by 43 and 24%, respectively while 2 mM of amytal caused 41 and 23% inhibition, respectively. There was no change in the ADP/O ratios. RO-28-2653 (50 μM) did not significantly alter the activity of the respiratory chain complexes or succinate dehydrogenase, although citrate synthase (CS) was inhibited by upto 71%. This inhibition was non-competitive at a Ki of 25±5 μM. Inhibitory effects in the presence of hydrophobic substances, such as BSA and Triton X-100, were significantly lower in both test systems. In conclusion, high concentrations of RO-28-2653 impair mitochondrial function, although compared to amytal and 2,4-DNP, this is rather low. The resultant impairment is less pronounced in the more complex skinned muscle fiber system, and is dependent on hydrophobic interactions. | ||
|keywords=2,4-Dinitrophenol, Amytal, Matrix metalloproteinases, Rat heart mitochondria, RO-28-2653 | |keywords=2,4-Dinitrophenol, Amytal, Matrix metalloproteinases, Rat heart mitochondria, RO-28-2653 | ||
|mipnetlab=DE Magdeburg Gellerich FN, | |mipnetlab=DE Magdeburg Gellerich FN, AT Innsbruck Oroboros | ||
|discipline=Pharmacology; Biotechnology | |discipline=Pharmacology; Biotechnology | ||
}} | }} | ||
{{Labeling | {{Labeling | ||
|organism=Rat | |||
|tissues=Heart | |||
|preparations=Permeabilized tissue, Isolated mitochondria | |||
|diseases=Cancer | |||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
|additional=Pharmacology; Biotechnology | |additional=Pharmacology; Biotechnology | ||
|discipline=Pharmacology; Biotechnology | |discipline=Pharmacology; Biotechnology | ||
}} | }} |
Latest revision as of 10:54, 23 January 2019
Opalka JR, Gellerich FN, Kling L, Müller-Beckmann B, Zierz S (2002) Effect of the new matrix metalloproteinase inhibitor RO-28-2653 on mitochondrial function. Biochem Pharmacol 63:725-32. |
Opalka JR, Gellerich FN, Kling L, Mueller-Beckmann B, Zierz S (2002) Biochem Pharmacol
Abstract: Matrix metalloproteinases (MMPs) have recently become interesting as potential anticancer drugs. RO-28-2653 is a promising compound because of its antimetastatic and antiangiogenic activities. Due to the structural similarity of RO-28-2653 to mitochondriotoxic agents, speculation has arisen that this substance might impair mitochondrial function. We, therefore, investigated the effects of RO-28-2653 on mitochondrial enzymes and on the functional properties of isolated mitochondria and skinned muscle fibers from rat hearts. Results were compared to the action of amytal and 2,4-dinitrophenol (2,4-DNP), both of which are well documented mitochondriotoxic compounds. In contrast to 2,4-DNP, RO-28-2653 did not uncouple oxidative phosphorylation, although higher concentrations of the compound did impair mitochondrial function. Using malate/pyruvate as substrate, 50 μM of RO-28-2653 inhibited mitochondrial respiration in isolated mitochondria and skinned fibers by 23 and 11%, respectively while 2 mM of amytal elicited almost complete inhibition of the mitochondrial respiration. RO-28-2653 (50 μM) inhibited succinate-dependent respiration in both systems by 43 and 24%, respectively while 2 mM of amytal caused 41 and 23% inhibition, respectively. There was no change in the ADP/O ratios. RO-28-2653 (50 μM) did not significantly alter the activity of the respiratory chain complexes or succinate dehydrogenase, although citrate synthase (CS) was inhibited by upto 71%. This inhibition was non-competitive at a Ki of 25±5 μM. Inhibitory effects in the presence of hydrophobic substances, such as BSA and Triton X-100, were significantly lower in both test systems. In conclusion, high concentrations of RO-28-2653 impair mitochondrial function, although compared to amytal and 2,4-DNP, this is rather low. The resultant impairment is less pronounced in the more complex skinned muscle fiber system, and is dependent on hydrophobic interactions. • Keywords: 2, 4-Dinitrophenol, Amytal, Matrix metalloproteinases, Rat heart mitochondria, RO-28-2653
• O2k-Network Lab: DE Magdeburg Gellerich FN, AT Innsbruck Oroboros
Labels:
Pathology: Cancer
Organism: Rat Tissue;cell: Heart Preparation: Permeabilized tissue, Isolated mitochondria
HRR: Oxygraph-2k
Pharmacology; Biotechnology