Opalka 2002 Biochem Pharmacol
|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.|
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
Labels: Pathology: Cancer
Organism: Rat Tissue;cell: Heart Preparation: Permeabilized tissue, Isolated mitochondria