Nonsteroidal antiinflammatory drugs cause apoptosis and induce cyclooxygenases in chicken embryo fibroblasts.

Lu, Xiaojun; Xie, Weilin; Reed, David W.; Bradshaw, William S.; Simmons, Denise R.

doi:10.1073/pnas.92.17.7961

Cited by 180 publications

(98 citation statements)

References 27 publications

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“…Similarly, apoptosis was induced by indomethacin at a lower concentration than aspirin. These findings are consistent with those reported in colon cancer and other cell lines (Lu et al, 1995;Shiff et al, 1996). Apoptosis is often accompanied by growth arrest.…”

Section: Discussionsupporting

confidence: 82%

Non-steroidal anti-inflammatory drug-induced apoptosis in gastric cancer cells is blocked by protein kinase C activation through inhibition of c-myc

et al. 1999

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Summary Apoptosis plays a major role in gastrointestinal epithelial cell turnover, ulcerogenesis and tumorigenesis. We have examined apoptosis induction by non-steroidal anti-inflammatory drugs (NSAIDs) in human gastric (AGS) cancer cells and the role of protein kinase C (PKC) and apoptosis-related oncogenes. After treatment with aspirin or indomethacin, cell growth was quantified by MTT assay, and apoptosis was determined by acridine orange staining, DNA fragmentation and flow cytometry. The mRNA and protein of p53, p21 waf1/cip1 and c-myc was detected by Northern and Western blotting respectively. The influence of PKC on indomethacin-induced apoptosis was determined by co-incubation of 12-O-tetradecanoylphorbol 13-acetate (TPA). The role of c-myc was determined using its antisense oligonucleotides. The results showed that both aspirin and indomethacin inhibited cell growth and induced apoptosis of AGS cells in a dose-and time-dependent manner, without altering the cell cycle. Indomethacin increased c-myc mRNA and protein, whereas p53 and p21 waf1/cip1 were unchanged. Down-regulation of c-myc by its antisense oligonucleotides reduced apoptosis induction by indomethacin. TPA could inhibit indomethacininduced apoptosis and accumulate cells in G 2 /M. Overexpression of c-myc was inhibited by TPA and p21 waf1/cip1 mRNA increased. In conclusion, NSAIDs induce apoptosis in gastric cancer cells which may be mediated by up-regulation of c-myc proto-oncogene. PKC activation can abrogate the effects of NSAIDs by decreasing c-myc expression.

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Section: Discussionsupporting

confidence: 82%

Non-steroidal anti-inflammatory drug-induced apoptosis in gastric cancer cells is blocked by protein kinase C activation through inhibition of c-myc

et al. 1999

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“…The NSAID indomethacin, itself a peroxisome proliferator (44,45), completely inhibited PGE 2 synthesis at a dose of 10 M but required 500-1000 M to induce strong COX-2 expression. Induction of COX-2 by NSAIDS has been reported previously (49) and is consistent with the structural similarity between PPs and NSAIDS (44,45). Thus, COX-2 induction by PPs is probably not a consequence of inhibited prostaglandin synthesis, but rather is probably due to the activation of immediate-early signaling pathways (36).…”

Section: Figsupporting

confidence: 69%

Induction of Cyclooxygenase-2 Expression by Peroxisome Proliferators and Non-tetradecanoylphorbol 12,13-Myristate-type Tumor Promoters in Immortalized Mouse Liver Cells

Ledwith¹,

Pauley²,

Wagner³

et al. 1997

Journal of Biological Chemistry

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Increased expression of cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostaglandin synthesis, has been associated with growth regulation and carcinogenesis in several systems. COX-2 is known to be induced by cytokines and the skin tumor promoter 12-tetradecanoylphorbol-13-myristate (TPA). In the present study, we investigated the effects of several non-TPA-type tumor promoters on COX-2 expression in immortalized mouse liver cells. Specifically, we tested peroxisome proliferators (PPs), which are rodent liver tumor promoters that cause gross alterations in cellular lipid metabolism, the rodent liver tumor promoter phenobarbital, and the skin tumor promoters okadaic acid and thapsigargin. The PPs Wy-14643, mono-ethylhexyl phthalate, clofibrate, ciprofibrate ethyl ester, and eicosatetraynoic acid each caused large increases in COX-2 mRNA and protein, with maximal expression seen approximately 10 h after treatment of quiescent cells. COX-2 expression was also induced by thapsigargin, okadaic acid, and calcium ionophore A23187, but not by phenobarbital or the steroid PP dehydroepiandrosterone sulfate. Induction of COX-2 expression generally resulted in increased synthesis of prostaglandin E 2 (PGE 2 ). However, the PPs caused little or no increase in PGE 2 levels, and they inhibited serum-induced PGE 2 synthesis. Unlike nonsteroidal anti-inflammatory drugs, the PPs do not directly inhibit cyclooxygenase enzyme activity in vitro. Thus, PPs regulate prostaglandin metabolism via both positive (COX-2 induction) and inhibitory mechanisms. In summary, the strong induction of COX-2 expression by PPs, thapsigargin, and okadaic acid suggests a possible role for COX-2 in the growth regulatory activity of these non-TPA-type tumor promoters.

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“…Rather intriguingly, since COX inhibition has been brought in connection with increased COX mRNA expression, it seems that one or more COX-produced metabolites of AA must act in a negative feedback mechanism on COX [45]. Finally, studies investigating the nature of regulatory factors controlling COX-2 expression identified reactive oxygen species (ROS)-mediated nuclear factor-κB (NF-κB) activation to play an active role [46,47], suggesting a positive feedback mechanism between expression levels of NF-κB and COX.…”

Section: The Cox Pathwaymentioning

confidence: 99%

Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis

Hyde

Missailidis

2009

International Immunopharmacology

146

101

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Lastly, the benefits of dietary omega-3 fatty acids and their mechanisms of action leading to reduced cancer risk and impeded cancer cell growth are mentioned. Finally, a proposal is put forward, suggesting a novel and integrated approach in viewing the molecular mechanisms and complex interactions responsible for the involvement of AA metabolites in carcinogenesis and the protective effects of omega-3 fatty acids in inflammation and tumour prevention.

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Nonsteroidal antiinflammatory drugs cause apoptosis and induce cyclooxygenases in chicken embryo fibroblasts.

Cited by 180 publications

References 27 publications

Non-steroidal anti-inflammatory drug-induced apoptosis in gastric cancer cells is blocked by protein kinase C activation through inhibition of c-myc

Non-steroidal anti-inflammatory drug-induced apoptosis in gastric cancer cells is blocked by protein kinase C activation through inhibition of c-myc

Induction of Cyclooxygenase-2 Expression by Peroxisome Proliferators and Non-tetradecanoylphorbol 12,13-Myristate-type Tumor Promoters in Immortalized Mouse Liver Cells

Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis

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