Celecoxib decreases mitochondrial complex IV activity and induces oxidative stress in isolated rat heart mitochondria: An analysis for its cardiotoxic adverse effect

Abstract

In spite of the cardiotoxic effect of selective cyclooxygenase-2 inhibitors, they are most widely used as anti-inflammatory and analgesic drugs. Today, valdecoxib and rofecoxib have been withdrawn in the market but celecoxib remains.In this study, we focused on an analysis of celecoxib toxic effects on isolated mitochondria. Isolated rat heart mitochondria were obtained using differential centrifugation. Using flow cytometry and biochemical assays, we searched succinate dehydrogenases, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) formation, mitochondrial swelling, ATP/ADP ratio, lipid peroxidation, and mitochondrial complexes activity in rat heart isolated mitochondria. Herein, our results indicated a significant decrease in the activity of complex IV after exposure with celecoxib (16 µg/ml). This decrease in the activity of complex IV is paralleled by the MMP collapse, ROS formation, mitochondrial swelling, depletion of ATP, and lipid peroxidation. For the first time, this introductory study has shown a significant decrease in the activity of complex IV and mitochondrial dysfunction after exposure with celecoxib in rat heart isolated mitochondria.

Cardioprotective role of royal jelly in the prevention of celecoxib-mediated cardiotoxicity in adult male albino rats

“…Respiratory chain enzyme (Complex IV) activity was significantly reduced following exposure to celecoxib. Parallel to this decline in complex IV activity, mitochondrial membrane potential (MMP) collapse, reactive oxygen species (ROS) production, mitochondrial swelling, ATP depletion, and lipid peroxidation occur [ 35 ].…”

Mitochondrial Dysfunction in Cardiac Diseases and Therapeutic Strategies

“…NSAID-induced cardiac cytotoxicity is caused by the induction of apoptotic signaling via a ROS-mediated shift in mitochondrial permeability [142]. Celecoxib, a selective cyclooxygenase-2 inhibitor, causes a decrease in complex IV activity accompanied by MMP collapse, ROS formation, mitochondrial swelling, ATP depletion, and lipid peroxidation [143].…”

Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation

“…Inhibition can be caused by directly inhibiting the activity of MRC complexes. For example, zoniporide [ 64 ], naproxen [ 60 , 138 ], dronedarone [ 139 ], and mubritinib [ 140 ] inhibit complex I; propranolol and atenolol disrupt complex II [ 119 ]; celecoxib suppresses complex IV [ 14 ]; and As 2 O 3 inhibits complex I, III, and IV [ 141 ]. OXPHOS may also be blocked by inhibition of the expression of MRC complexes, such as by mitoxantrone [ 100 ].…”

“…The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, including ICH S7B [ 9 ] and ICH E14 [ 10 ], were enacted to develop clinical and preclinical cardiotoxicity screening approaches in 2005, which significantly lowered the proportion of drugs with QT prolongation from 60% in 2005 to 10% in 2012 [ 11 ]. However, another 17 cardiotoxic drugs were withdrawn from the market following their implementation, including benfluorex (2009), rosiglitazone (2011), celecoxib (2011), ponatinib (2013), and etoricoxib, which have been reported to cause mitochondria dysfunction [ 12 , 13 , 14 , 15 , 16 ]. Thus far, 29% of withdrawn drugs have been reported to exhibit mitochondrial toxicity ( Table 1 ).…”