Relative non‐steroidal anti‐inflammatory drug (NSAID) antiproliferative activity is mediated through p21‐induced G1 arrest and E2F inhibition

Bock, Jonathan M.; Menon, Sarita G.; Goswami, Prabhat C.; Sinclair, Lori L.; Bedford, Nichole S.; Domann, Frederick E.; Trask, Douglas K.

doi:10.1002/mc.20318

Cited by 19 publications

(19 citation statements)

References 28 publications

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“…Treatment with this drug induced apoptosis in doxorubicin resistant breast cancer cells and potentiated apoptosis in the presence of other chemotherapeutic agents. Interestingly, there is also evidence that NSAIDS like piroxicam, naproxen, nimesulide and acetylsalicylic acid cause inhibition of c-AMP dependent activation of PKA and in a COX- independent manner (49, 50). These findings raise the potential of combination of NSAIDS alone or with canonical NF-κB p-p65 (Ser 536) inhibitors in future chemoprevention trials.…”

Section: Discussionmentioning

confidence: 99%

Nuclear NF-κB p65 Phosphorylation at Serine 276 by Protein Kinase A Contributes to the Malignant Phenotype of Head and Neck Cancer

Arun

Brown

Ehsanian

et al. 2009

Clinical Cancer Research

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Purpose: Aberrant nuclear activation and phosphorylation of the canonical NF-κB subunit RELA/p65 at Serine-536 by inhibitor κB kinase is prevalent in head and neck squamous cell carcinoma (HNSCC), but the role of other kinases in NF-κB activation has not been well defined. Here, we investigated the prevalence and function of p65-Ser276 phosphorylation by protein kinase A (PKA) in the malignant phenotype and gene transactivation, and studied p65-Ser276 as a potential target for therapy. Experimental Design: Phospho and total p65 protein expression and localization were determined in HNSCC tissue array and in cell lines. The effects of the PKA inhibitor H-89 on NF-κB activation, downstream gene expression, cell proliferation and cell cycle were examined. Knockdown of PKA by specific siRNA confirmed the specificity. Results: NF-κB p65 phosphorylated at Ser276 was prevalent in HNSCC and adjacent dysplastic mucosa, but localized to the cytoplasm in normal mucosa. In HNSCC lines, tumor necrosis factor-α (TNF-α) significantly increased, whereas H-89 inhibited constitutive and TNF-α-induced nuclear p65 (Ser276) phosphorylation, and significantly suppressed NF-κB and target gene IL-8 reporter activity. Knockdown of PKA by small interfering RNA inhibited NF-κB, IL-8, and BCL-XL reporter gene activities. H-89 suppressed cell proliferation, induced cell death, and blocked the cell cycle in G 1 -S phase. Consistent with its biological effects, H-89 down-modulated expression of NF-κB-related genes Cyclin D1, BCL2, BCL-XL, COX2, IL-8, and VEGF, as well as induced cell cycle inhibitor p21 CIP1/WAF1, while suppressing proliferative marker Ki67. NF-κB is a signal transcription factor that has emerged as an important modulator of altered gene expression programs and malignant phenotype in the development and progression of cancer. We reported previously that NF-κB is aberrantly activated and promotes altered expression of multiple genes important in the malignant phenotype of human and murine head and neck squamous cell carcinoma (HNSCC; ref. 1, 2). The canonical mechanism for NF-κB nuclear translocation and activation involves the phosphorylation and subsequent degradation of its cytoplasmic inhibitor κB (IκB) by a trimeric inhibitor-κ B kinase α/β/γ complex in response to a wide range of stimuli such as oncogenic viruses, carcinogens, growth factors, and cytokines. Degradation of IκB results in the liberation of the p65-p50 heterodimer for its translocation to the nucleus where it transactivates target genes (3). The classical pathway of activation of NF-κB by physical dissociation of p65-p50 subunits from IκBα and subsequent nuclear translocation has been well studied (4, 5), but the differential dynamics of NF-κB transactivation following the phosphorylation of p65 at various sites is increasingly being appreciated. There is evidence that inhibitor-κ B kinase and various other kinases induce phosphorylation of p65 at Ser 536, a posttranslational modification critical for the transactivation of NF-κB in response to var...

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Section: Discussionmentioning

confidence: 99%

Nuclear NF-κB p65 Phosphorylation at Serine 276 by Protein Kinase A Contributes to the Malignant Phenotype of Head and Neck Cancer

Arun

Brown

Ehsanian

et al. 2009

Clinical Cancer Research

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“…Treatment of aspirin in various cell lines has been found to decrease proteasome activity and increase accumulation of ubiquitylated proteins, which correlates with its effect on cell death [53]. Aspirin and other NSAIDs exposure also increases the intracellular accumulation of various proteasomal substrates which are pro-apoptotic, like Bax, IkB-a, p53, p21 waf1/Cip1 and p27 kip1 [46,47,53,55,56]. Increased accumulation of p27 kip1 or p21 waf1/Cip1 would result in cell cycle arrest at the G1/S phase and apoptosis.…”

Section: Inhibition Of Proteasome Function and Cell Cycle Arrestmentioning

confidence: 97%

NSAIDs and apoptosis

Jana

2008

Cell. Mol. Life Sci.

134

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Regular use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with decreased incidence of cancer of the colon and other gastrointestinal organs. The chemopreventive properties of NSAIDs are due to their ability to induce apoptosis. Both COX-2-dependent and COX-2-independent mechanisms are involved in NSAIDs-induced neoplastic growth. This article reviews the recent literature that has revealed various important mechanisms of NSAIDs-induced apoptosis.

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“…Also, this reduction was concentration dependent for 12 h (Timocin & Ila, 2015). In an another study, 200 mM FLB (48 h) lead to apoptosis in squamous cell carcinoma lines in vitro, inducing caspase-3 enzyme activity (Bock et al, 2007). Additionally, FLB was related to cytotoxicity by leading to LDH leakage in rat hepatocytes cultures (Jurima-Romet et al, 1994;Masubuchi et al, 1998).…”

Section: Discussionmentioning

confidence: 93%

In vitrocytogenetic evaluation of the particular combination of flurbiprofen and roxithromycin

Timocin

Hüsunet

Valipour

et al. 2016

Drug and Chemical Toxicology

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Flurbiprofen (FLB) (anti-inflammatory and analgesic drug) and roxithromycin (RXM) (antibiotic) were widely used in world wide. This study deals with investigation of genotoxicity, cytotoxicity, and oxidative stress effects of a particular combination of these drugs in human cultured lymphocytes. Also, DNA damaging-protective effects of combination of these drugs were analyzed on plasmid DNA. Human lymphocytes were treated with different concentrations (FLB + RXM; 10 μg/mL + 25 μg/mL, 15 μg/mL + 50 μg/mL, and 20 μg/mL + 100 μg/mL) of the drugs following by study of their genotoxic and cytotoxic effects by analysis of cytokinesis-block micronucleus test and nuclear division index, respectively. The effect of the combination in aspect of anti-oxidative and DNA damaging activity was evaluated on Pet-22b plasmid. According to our results, the combination of FLB and RXM did not show a notable genotoxic effect on cells. Although each of the substances had been shown as a cytotoxic agent by previous researchers, in this research, the combination of these drugs did not exhibit any adverse effect on cell division. FLB had DNA protection effect against HO while in combination with RXM had not the same effect on the plasmid.

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Relative non‐steroidal anti‐inflammatory drug (NSAID) antiproliferative activity is mediated through p21‐induced G1 arrest and E2F inhibition

Cited by 19 publications

References 28 publications

Nuclear NF-κB p65 Phosphorylation at Serine 276 by Protein Kinase A Contributes to the Malignant Phenotype of Head and Neck Cancer

Nuclear NF-κB p65 Phosphorylation at Serine 276 by Protein Kinase A Contributes to the Malignant Phenotype of Head and Neck Cancer

NSAIDs and apoptosis

In vitrocytogenetic evaluation of the particular combination of flurbiprofen and roxithromycin

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