Celecoxib inhibits mitochondrial O2 consumption, promoting ROS dependent death of murine and human metastatic cancer cells via the apoptotic signalling pathway

Pritchard, Rhys; Rodrı́guez-Enrı́quez, Sara; Pacheco-Velázquez, Silvia Cecilia; Bortnik, Vuk; Moreno‐Sánchez, Rafael; Ralph, Stephen John

doi:10.1016/j.bcp.2018.05.013

Cited by 59 publications

(49 citation statements)

References 77 publications

(72 reference statements)

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Section: Repurposing Drugs As Potent Pro‐oxidative Anticancer Agentsmentioning

confidence: 99%

“…Celecoxib (Figure ) is another approved drug well suited for redesign and repurposing as an anticancer drug because of its potent pro‐oxidative effects in promoting and potentiating ROS production in cancer cells to induce cell death . Celecoxib also targets the cancer mitochondrial ROS production to overload cancer cells, activating intrinsic apoptosis . Celecoxib treatment of isolated rat heart, liver, or hepatoma mitochondria was shown to directly induce abrupt respiratory chain inhibition and as a consequence was associated with rapid production of H 2 O 2 .…”

Section: Repurposing Drugs As Potent Pro‐oxidative Anticancer Agentsmentioning

confidence: 99%

“…So far, the exact target(s) within the mitochondria of cancer cells affected by celecoxib have not been defined. However, it is clear that celecoxib affects the ΔΨ m and can also, when applied at higher levels (50–100 μM) in acute short‐term exposures, inhibit the respiratory complex I, II, and III and ATP production, albeit requiring greater micromolar concentrations than the low micromolar concentrations sufficient to promote significantly increased mitochondrial ROS production . Hence, its targets are most assuredly linked to the mitochondrial antioxidative systems.…”

Section: Repurposing Drugs As Potent Pro‐oxidative Anticancer Agentsmentioning

confidence: 99%

“…179,180 Celecoxib also targets the cancer mitochondrial ROS production to overload cancer cells, activating intrinsic apoptosis. 179 Celecoxib treatment of isolated rat heart, liver, or hepatoma mitochondria was shown to directly induce abrupt respiratory chain inhibition and as a consequence was associated with rapid production of H 2 O 2 . 179 This most likely proceeds via superoxide produced as a by-product of the respiratory chain because in whole cancer cells treated with celecoxib, significant levels of superoxide production could be detected rapidly occurring within minutes of addition of low (5 μM) levels.…”

Section: Repurposing Celecoxib (Celebrex) As a Potent Pro-oxidativementioning

confidence: 99%

“…However, it is clear that celecoxib affects the ΔΨ m and can also, when applied at higher levels (50-100 μM) in acute short-term exposures, inhibit the respiratory complex I, II, and III and ATP production, albeit requiring greater micromolar concentrations than the low micromolar concentrations sufficient to promote significantly increased mitochondrial ROS production. 179 Hence, its targets are most assuredly linked to the mitochondrial antioxidative systems. Celecoxib has also been established as a drug that kills CSCs (IC 50 approximately 20-30 μM for human breast cancer or rat hepatoma CSCs), suppresses CSC self-renewal, sensitizes against chemoresistance, inhibits epithelial to mesenchymal transition, and attenuates metastasis and tumorigenesis.…”

Section: Repurposing Celecoxib (Celebrex) As a Potent Pro-oxidativementioning

confidence: 99%

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Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers

Ralph

Nozuhur

ALHulais

et al. 2019

Medicinal Research Reviews

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Over the last decade, three major advances have contributed in improving the response rates against cancer including, immunotherapy; greater understanding of the molecular, biochemical, and cellular mechanisms in carcinogenesis thereby providing drug targets; and identification of reliable biomarkers for early detection to facilitate the earlier stage treatment of disease. However, no single universal cancer cure has yet been found, although combinations from the above areas have steadily improved survival outcomes. Hence, chemotherapy remains a key component in the oncologist's arsenal for cancer therapy, despite frequent development of drug resistance and more aggressive cancers with onset of advanced stage metastases. The focus here is to explore the repurposing of old drugs that cause pro‐oxidative overload to overcome onset of resistance to chemotherapy and enhance chemotherapeutic responses, particularly against metastatic cancer. Excellent examples of US Food and Drug Administration approved drugs suitable for repurposing are the potent and specific thioreductase inhibitor auranofin and the nonsteroidal anti‐inflammatory drug, celecoxib. Recently, both drugs were shown to selectively target and kill metastatic cancer cells and cancer stem cells (CSCs), predominantly by promoting excessive mitochondrial reactive oxygen species. Thus, targeting intracellular redox systems of advanced stage metastatic cancer cells and CSCs can promote an overload of pro‐oxidative stress to activate the intrinsic pathway for programmed cell death. It is envisaged that more clinical studies will incorporate longer term use of repurposed drugs, such as auranofin or celecoxib, to target redox systems in cancer cells as part of common practice postcancer diagnosis, providing enhanced chemotherapeutic responses and increased cancer survival.

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Section: Repurposing Drugs As Potent Pro‐oxidative Anticancer Agentsmentioning

confidence: 99%

Section: Repurposing Drugs As Potent Pro‐oxidative Anticancer Agentsmentioning

confidence: 99%

Section: Repurposing Drugs As Potent Pro‐oxidative Anticancer Agentsmentioning

confidence: 99%

Section: Repurposing Celecoxib (Celebrex) As a Potent Pro-oxidativementioning

confidence: 99%

Section: Repurposing Celecoxib (Celebrex) As a Potent Pro-oxidativementioning

confidence: 99%

See 3 more Smart Citations

Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers

Ralph

Nozuhur

ALHulais

et al. 2019

Medicinal Research Reviews

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ADT‐OH synergistically enhanced the antitumor activity of celecoxib in human colorectal cancer cells

et al. 2023

Cancer Medicine

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BackgroundColorectal cancer is one of the most prevalent cancers in the world, but the research on its prevention, early diagnosis and treatment is still a major challenge in clinical oncology. Thus, there is a pressing requirement to find effective strategies to improve the survival of colon cancer patients.MethodsCelecoxib has been accounted to be an effective antitumor drug, but may exhibit significant side effects. In recent studies, 5‐(4‐hydroxyphenyl)‐3H‐1,2‐dithiole‐3‐thione (ADT‐OH), one of the most commonly used reagents for the synthesis of sustained‐release H2S donors, has also been reported to inhibit cancer progression by affecting processes such as cell cycle, angiogenesis, and apoptosis. Therefore, we evaluated the therapeutic effect of the combination of ADT‐OH and celecoxib on colorectal cancer through in vitro and in vivo, hoping to achieve better therapeutic effect and reduce the effect of celecoxib on gastric injury through exogenous administration of H2S.ResultsOur results demonstrated that ADT‐OH combined with celecoxib synergistically inhibited the proliferation and migration ability of human colorectal cancer HCT116 cells, altered cell cycle and cytoskeleton, increased intracellular reactive oxygen species (ROS), and promoted cell apoptosis. Noteworthy, in vivo studies also indicated the excellent antitumor therapeutic effect of the combination therapy without apparent toxicity.ConclusionsIn general, our results provide a reasonable combination strategy of low‐dose ADT‐OH and celecoxib in the preclinical application of colorectal cancer.

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Predominant factors influencing reactive oxygen species in cancer stem cells

Soundararajan,

Warrier,

Dharmarajan

et al. 2023

J of Cellular Biochemistry

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Reactive oxygen species (ROS) and its related signaling pathways and regulating molecules play a major role in the growth and development of cancer stem cells. The concept of ROS and cancer stem cells (CSCs) has been gaining much attention since the past decade and the evidence show that these CSCs possess robust self‐renewal and tumorigenic potential and are resistant to conventional chemo‐ and radiotherapy and believed to be responsible for tumor progression, metastasis, and recurrence. It seems reasonable to say that cancer can be cured only if the CSCs are eradicated. ROS are Janus‐faced molecules that can regulate cellular physiology as well as induce cytotoxicity, depending on the magnitude, duration, and site of generation. Unlike normal cancer cells, CSCs expel ROS efficiently by upregulating ROS scavengers. This unique redox regulation in CSCs protects them from ROS‐mediated cell death and nullifies the effect of radiation, leading to chemoresistance and radioresistance. However, how these CSCs control ROS production by scavenging free radicals and how they maintain low levels of ROS is a challenging to understand and these attributes make CSCs as prime therapeutic targets. Here, we summarize the mechanisms of redox regulation in CSCs, with a focus on therapy resistance, its various pathways and microRNAs regulation, and the potential therapeutic implications of manipulating the ROS levels to eradicate CSCs. A better understanding of these molecules, their interactions in the CSCs may help us to adopt proper control and treatment measures.

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Celecoxib inhibits mitochondrial O2 consumption, promoting ROS dependent death of murine and human metastatic cancer cells via the apoptotic signalling pathway

Cited by 59 publications

References 77 publications

Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers

Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers

ADT‐OH synergistically enhanced the antitumor activity of celecoxib in human colorectal cancer cells

Predominant factors influencing reactive oxygen species in cancer stem cells

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