Molecular mechanism of diclofenac-induced apoptosis of promyelocytic leukemia: dependency on reactive oxygen species, akt, bid, cytochrome and caspase pathway

Inoue, Akiko; Muranaka, Shikibu; Fujita, Hirofumi; Kanno, Tomoko; Tamai, Hiroshi; Utsumi, Kozo

doi:10.1016/j.freeradbiomed.2004.07.003

Cited by 99 publications

(51 citation statements)

References 28 publications

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“…Uncoupling of respiration by diclofenac is thought to be responsible for mitochondrial dysfunction. Although a collapse of the mitochondrial membrane potential after diclofenac exposure has been described in mammalian cells (Bort et al, 1999;Inoue et al, 2004;Lim et al, 2006;Masubuchi et al, 2002), this can also be the result of opening of the MPT pore instead of uncoupling. Here, we followed the effect of diclofenac on pH cyt and pH mit over time.…”

Section: Discussionmentioning

confidence: 99%

“…In several cellular systems, including human hepatocytes, diclofenac can induce ROS formation that causes successive opening of the MPT pore, cytochrome c release, caspase activation and apoptosis (Gó mez-Lechó n et al , 2003;Inoue et al, 2004;Lim et al, 2006). As the respiratory chain is a well-known source of ROS (Kowaltowski et al, 2009;Poyton et al, 2009), we studied the role of respiration in diclofenac-induced ROS formation.…”

Section: Discussionmentioning

confidence: 99%

“…This leads to decreased ATP production and ATP depletion (Bort et al, 1999;Masubuchi et al, 2002). Furthermore, in several cellular systems, including human hepatocytes, diclofenac induces ROS formation, causing successive opening of the MPT pore, cytochrome c release, caspase activation and apoptosis (Gó mez-Lechó n et al, 2003;Inoue et al, 2004;Lim et al, 2006). However, the primary cause of the mitochondrial dysfunction remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Subunits Rip1p and Cox9p of the respiratory chain contribute to diclofenac-induced mitochondrial dysfunction

et al. 2011

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The widely used drug diclofenac can cause serious heart, liver and kidney injury, which may be related to its ability to cause mitochondrial dysfunction. Using Saccharomyces cerevisiae as a model system, we studied the mechanisms of diclofenac toxicity and the role of mitochondria therein. We found that diclofenac reduced cell growth and viability and increased levels of reactive oxygen species (ROS). Strains increasingly relying on respiration for their energy production showed enhanced sensitivity to diclofenac. Furthermore, oxygen consumption was inhibited by diclofenac, suggesting that the drug inhibits respiration. To identify the site of respiratory inhibition, we investigated the effects of deletion of respiratory chain subunits on diclofenac toxicity. Whereas deletion of most subunits had no effect, loss of either Rip1p of complex III or Cox9p of complex IV resulted in enhanced resistance to diclofenac. In these deletion strains, diclofenac did not increase ROS formation as severely as in the wild-type. Our data are consistent with a mechanism of toxicity in which diclofenac inhibits respiration by interfering with Rip1p and Cox9p in the respiratory chain, resulting in ROS production that causes cell death.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Subunits Rip1p and Cox9p of the respiratory chain contribute to diclofenac-induced mitochondrial dysfunction

et al. 2011

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“…DS causes apoptosis in hepatocytes by an oxidative stress-induced opening of the mitochondrial permeability transition pore (G ó mez-Lech ó n et al 2003). The molecular mechanism of DS-induced apoptosis involves the generation of ROS as an initial step (Inoue et al 2004, Milusheva et al 2008. It is known that oxidative stress damages proteins, lipids and nucleic acids, which result in cell membrane and synaptic disorganization, and neural cell signaling dysfunction as a consequence of apoptotic and/or necrotic events (Cui et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Effects of prenatal exposure to diclofenac sodium and saline on the optic nerve of 4- and 20-week-old male rats: a stereological and histological study

Çolakoğlu

Aktaş

Raimondo

et al. 2013

Biotechnic & Histochemistry

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We investigated the effects of diclofenac sodium (DS) on development of the optic nerve in utero . Pregnant female rats were separated into three groups: control, saline treated and DS treated. Offspring of these animals were divided into 4-week-old and 20-week-old groups. At the end of the 4th and 20th weeks of postnatal life, the animals were sacrifi ced, and right optic nerves were excised and sectioned for ultrastructural and stereological analyses. We demonstrated that both DS and saline produced structural and morphometric changes in the total axon number and density of axons, but decreased the myelin sheath thickness in male optic nerves. All ultrastructural and morphometric features were well developed in 20-week-old rats. We showed that development of the optic nerve continues during the early postnatal period and that some compensation for exposure to deleterious agents in utero may occur during early postnatal life.

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“…Apart from diclofenac metabolites, the parent compound has also been demonstrated to target mitochondria and induce mitochondrial dysfunction [98–100]. Specifically, in isolated liver mitochondria, diclofenac readily inhibits ATP synthesis and induces the MPT [94, 97], leading to a collapse of the mitochondrial transmembrane potential (ΔΨ m ).…”

Section: Diclofenac Hepatotoxicitymentioning

confidence: 99%

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

et al. 2018

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Mitochondria are critical cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling. Their central role in energy metabolism, as well as their high abundance in hepatocytes, make them important targets for drug-induced hepatotoxicity. This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen, diclofenac, anti-tuberculosis drugs such as rifampin and isoniazid, anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids. The utilization of circulating mitochondrial-specific biomarkers in understanding mechanisms of toxicity in humans will also be examined. In summary, it is well-established that mitochondria are central to acetaminophen-induced cell death. However, the most promising areas for clinically useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis, In contrast, the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans. Development of clinically relevant animal models and more translational studies using mechanistic biomarkers are critical for progress in this area.

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Molecular mechanism of diclofenac-induced apoptosis of promyelocytic leukemia: dependency on reactive oxygen species, akt, bid, cytochrome and caspase pathway

Cited by 99 publications

References 28 publications

Subunits Rip1p and Cox9p of the respiratory chain contribute to diclofenac-induced mitochondrial dysfunction

Subunits Rip1p and Cox9p of the respiratory chain contribute to diclofenac-induced mitochondrial dysfunction

Effects of prenatal exposure to diclofenac sodium and saline on the optic nerve of 4- and 20-week-old male rats: a stereological and histological study

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

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