Reactive oxygen species mediate tolfenamic acid-induced apoptosis in human colorectal cancer cells

Jeong, Jin Boo; Choi, Jieun; Baek, Seung Joon; Lee, Seong-Ho

doi:10.1016/j.abb.2013.07.016

Cited by 26 publications

(24 citation statements)

References 52 publications

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“…Earlier studies revealed that Cur and TA have the ability to increase ROS in cancer cells [45, 46]. Our results demonstrate that the combination of TA and Cur resulted in increased ROS levels compared to single drug treatment (Figure 5).…”

Section: Discussionsupporting

confidence: 68%

“…Both Cur and TA have been shown to increase ROS levels in L3.6pl cells. Both Cur [45] and TA [46] are known to generate ROS and cause subsequent DNA damage via modulating transcription factors [46] and/or microRNAs (miR-27a and miR-20a) [45]. Since both agents can induce ROS, the combination can further potentiate such response in susceptible cells.…”

Section: Discussionmentioning

confidence: 99%

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Small molecule tolfenamic acid and dietary spice curcumin treatment enhances antiproliferative effect in pancreatic cancer cells via suppressing Sp1, disrupting NF-kB translocation to nucleus and cell cycle phase distribution

Basha

Connelly

Sankpal

et al. 2016

The Journal of Nutritional Biochemistry

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Combination of dietary/herbal spice curcumin (Cur) and COX inhibitors has been tested for improving therapeutic efficacy in pancreatic cancer (PC). The objective of this study was to identify agent with low toxicity and COX-independent mechanism to induce PC cell growth inhibition when used along with Cur. Anti-cancer NSAID, Tolfenamic acid (TA) and Cur combination was evaluated using PC cell lines. L3.6pl and MIA PaCa-2 cells were treated with Cur (5–25 μM) or TA (25–100 μM) or combination of Cur (7.5 μM) and TA (50 μM). Cell viability was measured at 24–72 h post-treatment using CellTiter-Glo kit. While both agents showed a steady/consistent effect, Cur+TA caused higher growth inhibition. Anti-proliferative effect was compared with COX inhibitors, Ibuprofen and Celebrex. Cardiotoxicity was assessed using cordiomyocytes (H9C2). The expression of Sp proteins, survivin, and apoptotic markers (Western blot), caspase 3/7 (caspase-Glo kit), Annexin-V staining (flow cytometry), reactive oxygen species (ROS) and cell cycle phase distribution (flow cytometry) were measured. Cells were treated with TNF-α and NF-kB translocation from cytoplasm to nucleus was evaluated (immunofluorescence). When compared to individual agents, combination of Cur+TA caused significant increase in apoptotic markers, ROS levels and augmented NF-kB translocation to nucleus. TA caused cell cycle arrest in G0/G1 and the combination treatment showed mostly DNA synthesis phase arrest. These results suggest that combination of Cur+TA is less toxic and effectively enhance the therapeutic efficacy in PC cells via COX-independent mechanisms.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Small molecule tolfenamic acid and dietary spice curcumin treatment enhances antiproliferative effect in pancreatic cancer cells via suppressing Sp1, disrupting NF-kB translocation to nucleus and cell cycle phase distribution

Basha

Connelly

Sankpal

et al. 2016

The Journal of Nutritional Biochemistry

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“…Reactive oxygen species played a role as an important inhibitor of cancer cell proliferation and in induction of apoptosis . As treatment of ursolic acid and oxaliplatin promoted apoptosis and inhibited CRC cell proliferation, we examined the ROS production in treated cells.…”

Section: Resultsmentioning

confidence: 99%

Ursolic acid enhances the therapeutic effects of oxaliplatin in colorectal cancer by inhibition of drug resistance

et al. 2017

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It has been reported that ursolic acid has anti‐tumor activity and it enhances the therapeutic effect of oxaliplatin in colorectal cancer (CRC). However, the underlying mechanisms remain unknown. In the present study, the mechanisms of the enhancement of therapeutic effects through use of ursolic acid were investigated. We treated CRC cell lines HCT8 and SW480 with ursolic acid and oxaliplatin and monitored the effects on cell proliferation, apoptosis, reactive oxygen species (ROS) production and drug resistance gene production. We discovered that treatment with a combination of ursolic acid and oxaliplatin resulted in significant inhibition of cell proliferation, significantly increased apoptosis and ROS production, and significant inhibition of drug resistance gene expression. Our study provided evidence that ursolic acid enhances the therapeutic effects of oxaliplatin in colorectal cancer by ROS‐mediated inhibition of drug resistance.

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“…Emerging evidence suggest that mitogen-activated protein kinases (MAPKs) participate in the regulation of NF-κB activation. Our early observation showed that the TA-induced ROS generation results in ERK activation and DNA damage and thereby NF-κB and ATF3 activation, and eventually apoptosis in human colorectal cancer cells ( Jeong et al ., 2013a ). However, in this study we found that TA specifically blocks the TNF-α- and LPS-induced JNK phosphorylation ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Tolfenamic Acid Suppresses Inflammatory Stimuli-Mediated Activation of NF-κB Signaling

Shao

Lou

Jeong

et al. 2015

Biomolecules & Therapeutics

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Tolfenamic acid (TA) is a traditional non-steroid anti-inflammatory drug (NSAID) and has been broadly used for the treatment of migraines. Nuclear factor kappa B (NF-κB) is a sequence-specific transcription factor and plays a key role in the development and progression of inflammation and cancer. We performed the current study to investigate the underlying mechanisms by which TA suppresses inflammation focusing on NF-κB pathway in TNF-α stimulated human normal and cancer cell lines and lipopolysaccharide (LPS)-stimulated mouse macrophages. Different types of human cells (HCT116, HT-29 and HEK293) and mouse macrophages (RAW264.7) were pre-treated with different concentrations of TA and then exposed to inflammatory stimuli such as TNF-α and LPS. Transcriptional activity of NF-κB, IκB-α-degradation, p65 translocation and mitogen-activated protein kinase (MAPK) activations were measured using luciferase assay and Western blots. Pre-treatment of TA repressed TNF-α- or LPS-stimulated NF-κB transactivation in a dose-dependent manner. TA treatment reduced degradation of IκB-α and subsequent translocation of p65 into nucleus. TA significantly down-regulated the phosphorylation of c-Jun N-terminal kinase (JNK). However, TA had no effect on NF-κB signaling and JNK phosphorylation in HT-29 human colorectal cancer cells. TA possesses anti-inflammatory activities through suppression of JNK/NF-κB pathway in different types of cells.

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Reactive oxygen species mediate tolfenamic acid-induced apoptosis in human colorectal cancer cells

Cited by 26 publications

References 52 publications

Small molecule tolfenamic acid and dietary spice curcumin treatment enhances antiproliferative effect in pancreatic cancer cells via suppressing Sp1, disrupting NF-kB translocation to nucleus and cell cycle phase distribution

Small molecule tolfenamic acid and dietary spice curcumin treatment enhances antiproliferative effect in pancreatic cancer cells via suppressing Sp1, disrupting NF-kB translocation to nucleus and cell cycle phase distribution

Ursolic acid enhances the therapeutic effects of oxaliplatin in colorectal cancer by inhibition of drug resistance

Tolfenamic Acid Suppresses Inflammatory Stimuli-Mediated Activation of NF-κB Signaling

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