Effect of the new matrix metalloproteinase inhibitor RO-28-2653 on mitochondrial function

• Published in: Biochemical pharmacology 2002-02, Vol.63 (4), p.725-732
• Main Authors: Opalka, Jens R., Gellerich, Frank N., Kling, Lothar, Müller-Beckmann, Bernd, Zierz, Stephan
• Format: Article
• Language: English
• Subjects: 2,4-Dinitrophenol; Amytal; Animals; Antineoplastic agents; Biological and medical sciences; Enzyme Inhibitors - pharmacology; General aspects; Male; Matrix Metalloproteinase Inhibitors; Matrix metalloproteinases; Matrix Metalloproteinases - metabolism; Medical sciences; Mitochondria, Heart - drug effects; Mitochondria, Heart - enzymology; Pharmacology. Drug treatments; Piperazines - pharmacology; Pyrimidines - pharmacology; Rat heart mitochondria; Rats; Rats, Wistar; Respiration - drug effects; RO-28-2653
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(01)00867-X

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 K i 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.