The Proapoptotic Effect of Traditional and Novel Nonsteroidal Anti-Inflammatory Drugs in Mammalian and Yeast Cells

Farrugia, Gianluca; Balzan, Rena

doi:10.1155/2013/504230

Cited by 14 publications

(14 citation statements)

References 165 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Earlier reports suggest differential cytokine regulation by aspirin in different cells [ 32 ]. Aspirin has been reported to be a potential chemopreventive and antiproliferative NSAID functioning via COX-independent pathways which are presumably associated with increased oxidative stress and mitochondrial dysfunction [ 35 – 36 ]. Our results have also indicated a lower GSH pool, particularly in the mitochondria, and a compromised GSH-dependent redox metabolism after LPS and ASA treatment which was partially or completely recovered after NAC treatment.…”

Section: Discussionmentioning

confidence: 99%

Potentiation of LPS-Induced Apoptotic Cell Death in Human Hepatoma HepG2 Cells by Aspirin via ROS and Mitochondrial Dysfunction: Protection by N-Acetyl Cysteine

2016

View full text Add to dashboard Cite

Cytotoxicity and inflammation-associated toxic responses have been observed to be induced by bacterial lipopolysaccharides (LPS) in vitro and in vivo respectively. Use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, has been reported to be beneficial in inflammation-associated diseases like cancer, diabetes and cardiovascular disorders. Their precise molecular mechanisms, however, are not clearly understood. Our previous studies on aspirin treated HepG2 cells strongly suggest cell cycle arrest and induction of apoptosis associated with mitochondrial dysfunction. In the present study, we have further demonstrated that HepG2 cells treated with LPS alone or in combination with aspirin induces subcellular toxic responses which are accompanied by increase in reactive oxygen species (ROS) production, oxidative stress, mitochondrial respiratory dysfunction and apoptosis. The LPS/Aspirin induced toxicity was attenuated by pre-treatment of cells with N-acetyl cysteine (NAC). Alterations in oxidative stress and glutathione-dependent redox-homeostasis were more pronounced in mitochondria compared to extra- mitochondrial cellular compartments. Pre-treatment of HepG2 cells with NAC exhibited a selective protection in redox homeostasis and mitochondrial dysfunction. Our results suggest that the altered redox metabolism, oxidative stress and mitochondrial function in HepG2 cells play a critical role in LPS/aspirin-induced cytotoxicity. These results may help in better understanding the pharmacological, toxicological and therapeutic properties of NSAIDs in cancer cells exposed to bacterial endotoxins.

show abstract

Section: Discussionmentioning

confidence: 99%

Potentiation of LPS-Induced Apoptotic Cell Death in Human Hepatoma HepG2 Cells by Aspirin via ROS and Mitochondrial Dysfunction: Protection by N-Acetyl Cysteine

2016

View full text Add to dashboard Cite

show abstract

“…NSAIDs can also mediate apoptosis by inducing the activation of caspases, a family of proapoptotic cysteine proteinases which typically exist as latent zymogens in cells. Activation of these proteins by proapoptotic signals initiates a caspase cascade whereby initiator caspases specifically activate other executioner-type caspases [41].…”

Section: Molecular Mechanisms For How N-3 Pufas Rescue Patients From mentioning

confidence: 99%

“…NSAIDs can induce damage or apoptosis by upregulating the generation of reactive oxygen species (ROS) and by inducing oxidative stress coupled with many proapoptotic signals such as nuclear factor jB inhibition and mitogenactivated protein kinase activation [41]. However, the cellular prooxidant behavior of NSAIDs has often been the subject of controversy owing to conflicting reports that NSAIDs such as indomethacin and sulindac scavenge ROS and exert a cytoprotective and antioxidant effect in cells [68,69].…”

Section: Enhancing Host Defense Phase 2 Enzyme Responsementioning

confidence: 99%

Omega-3 polyunsaturated fatty acids as an angelus custos to rescue patients from NSAID-induced gastroduodenal damage

et al. 2015

View full text Add to dashboard Cite

Nonsteroidal anti-inflammat ory drugs (NSAIDs) are one of the drug types frequently prescribed for their analgesic, anti-inflammatory, and antithrombotic actions, but carry a risk of major gastroduodenal damage from mild erosive changes to serious ulceration leading to fatal outcomes. From the long history of willow tree bark and its extracts being applied for the relief of pain and fever, the synthesis of acetylsalicylic acid, the development of selective cyclooxygenase 2 inhibitors (coxibs), and the identification of a G-protein-coupled receptor for prostaglandin, the popular combination regimen of an NSAID and a proton pump inhibitor was invented, but development was continued for further improvement. With regard to major NSAID adverse effects, gastrointestinal (GI) and cardiovascular (CV) risks still remained as problems to be solved. In this review, it is shown that n-3 polyunsaturated fatty acid (PUFA) based NSAIDs can be an angelus custos, supported with facts that an intake of essential n-3 PUFAs orchestrates concerted protective actions against two notorious side effects of NSAIDs, the aforementioned GI risk and CV risk of NSAIDs. Since pills containing n-3 PUFAs, omega-3-acid ethyl ester capsules (Lovaza, Omarcor), have already been safely prescribed to prevent atherosclerosis through lessening lipid burdening, the introduction of a drug delivery system such as a gastroretentive form of n-3 PUFA based NSAIDs will highlight newer hope for GI safety under the guarantee of reduced CV risk. Because n-3 PUFAs have been proven to attenuate cytotoxicity, inhibit lipid-raft-associated harmful signaling, and relieve oxidative stress relevant to NSAIDs, n-3 PUFA based NSAIDs will be next-generation GI-safe NSAIDs.

show abstract

“…The enhanced effectiveness of ATB-346 in reducing polyp formation in APCMin+ mice is likely due to the H 2 S released from this drug. In support of this statement, there are a number of reports that H 2 S donors and NSAID-H 2 S conjugates reduced the incidence and/or severity of cancer in a range of animal models and cell lines, including cell lines that do not express COX [ 27 – 30 , 37 ]. On the other hand, administration of TBZ (the H 2 S-releasing moiety of ATB-346) did not significantly affect the polyp score at either dose tested (see Fig 2 ).…”

Section: Discussionmentioning

confidence: 99%

Profound Chemopreventative Effects of a Hydrogen Sulfide-Releasing NSAID in the APCMin/+ Mouse Model of Intestinal Tumorigenesis

et al. 2016

View full text Add to dashboard Cite

Nonsteroidal anti-inflammatory drugs have been shown to reduce the incidence of gastrointestinal cancers, but the propensity of these drugs to cause ulcers and bleeding limits their use. H2S has been shown to be a powerful cytoprotective and anti-inflammatory substance in the digestive system. This study explored the possibility that a H2S-releasing nonsteroidal anti-inflammatory drug (ATB-346) would be effective in a murine model of hereditary intestinal cancer (APCMin+ mouse) and investigated potential mechanisms of action via transcriptomics analysis. Daily treatment with ATB-346 was significantly more effective at preventing intestinal polyp formation than naproxen. Significant beneficial effects were seen with a treatment period of only 3–7 days, and reversal of existing polyps was observed in the colon. ATB-346, but not naproxen, significantly decreased expression of intestinal cancer-associated signaling molecules (cMyc, β-catenin). Transcriptomic analysis identified 20 genes that were up-regulated in APCMin+ mice, 18 of which were reduced to wild-type levels by one week of treatment with ATB-346. ATB-346 is a novel, gastrointestinal-sparing anti-inflammatory drug that potently and rapidly prevents and reverses the development of pre-cancerous lesions in a mouse model of hereditary intestinal tumorigenesis. These effects may be related to the combined effects of suppression of cyclooxygenase and release of H2S, and correction of most of the APCMin+-associated alterations in the transcriptome. ATB-346 may represent a promising agent for chemoprevention of tumorigenesis in the GI tract and elsewhere.

show abstract

The Proapoptotic Effect of Traditional and Novel Nonsteroidal Anti-Inflammatory Drugs in Mammalian and Yeast Cells

Cited by 14 publications

References 165 publications

Potentiation of LPS-Induced Apoptotic Cell Death in Human Hepatoma HepG2 Cells by Aspirin via ROS and Mitochondrial Dysfunction: Protection by N-Acetyl Cysteine

Potentiation of LPS-Induced Apoptotic Cell Death in Human Hepatoma HepG2 Cells by Aspirin via ROS and Mitochondrial Dysfunction: Protection by N-Acetyl Cysteine

Omega-3 polyunsaturated fatty acids as an angelus custos to rescue patients from NSAID-induced gastroduodenal damage

Profound Chemopreventative Effects of a Hydrogen Sulfide-Releasing NSAID in the APCMin/+ Mouse Model of Intestinal Tumorigenesis

Contact Info

Product

Resources

About