Biology of Cox-2: An Application in Cancer Therapeutics

INSERM U-955, Team No. 10, Institut Mondor de Recherche Biomédicale, Université Paris Est, 94010 Créteil, Paris, France.
Current drug targets (Impact Factor: 3.02). 03/2011; 12(7):1082-93. DOI: 10.2174/138945011795677764
Source: PubMed


Cyclooxygenase-2 (Cox-2) is an inducible enzyme involved in the conversion of arachidonic acid to prostaglandin and other eicosanoids. Molecular pathology studies have revealed that Cox-2 is over-expressed in cancer and stroma cells during tumor progression, and anti-cancer chemo-radiotherapies induce expression of Cox-2 in cancer cells. Elevated tumor Cox-2 is associated with increased angiogenesis, tumor invasion and promotion of tumor cell resistance to apoptosis. Several experimental and clinical studies have established potent anti-cancer activity of NSAID (Non-steroidal anti-inflammatory drugs) and other Cox-2 inhibitors such as celecoxib. Much attention is being focused on Cox-2 inhibitors as beneficial target for cancer chemotherapy. The mode of action of Cox-2 and its inhibitors remains unclear. Further clinical application needs to be investigated for comprehending Cox-2 biological functions and establishing it as an effective target in cancer therapy.

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    • "NSAIDs are known as potent anti-inflammatory agents that act through the inhibition of the COX enzyme and the subsequent inhibition of prostaglandins which are catalysed by COX enzymes at the site of inflammation [45]. This type of drug is usually accompanied by side effects; however, some studies have suggested that selective COX-2 inhibitors such as celecoxib may produce superior anti-inflammatory drugs with substantial safety advantages over existing NSAIDs [46]. "
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    ABSTRACT: Toad glandular secretions and skin extractions contain many natural agents which may provide a unique resource for novel drug development. The dried secretion from the auricular and skin glands of Chinese toad (Bufo bufo gargarizans) is named Chansu, which has been used in Traditional Chinese Medicine (TCM) for treating infection and inflammation for hundreds of years. The sterilized hot water extraction of dried toad skin is named Huachansu (Cinobufacini) which was developed for treating hepatitis B virus (HBV) and several types of cancers. However, the mechanisms of action of Chansu, Huachansu, and their constituents within are not well reported. Existing studies have suggested that their anti-inflammation and anticancer potential were via targeting Nuclear Factor (NF)-κB and its signalling pathways which are crucial hallmarks of inflammation and cancer in various experimental models. Here, we review some current studies of Chansu, Huachansu, and their compounds in terms of their use as both anti-inflammatory and anticancer agents. We also explored the potential use of toad glandular secretions and skin extractions as alternate resources for treating human cancers in combinational therapies.
    Evidence-based Complementary and Alternative Medicine 03/2014; 2014:312684. DOI:10.1155/2014/312684 · 1.88 Impact Factor
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    • "However, the study presented here unexpectedly showed that hTERT knocking down led to a significant increase in COX2 expression, a well-defined oncogenic promoter, in gastric, cervical and breast cancer cells. Cyclooxygenase 2 is a rate-limiting enzyme in the production of diverse prostanoids with potent biological activities and induces oncogenesis by promoting cell proliferation and resistance to apoptosis (Wang and Dubois, 2004; Sobolewski et al, 2010; Wu et al, 2010; Chen et al, 2011; Khan et al, 2011). Given these facts, it is thus of importance to define the functional significance of COX2 upregulation in hTERTdepleted cancer cells. "
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    ABSTRACT: Background: Telomerase and telomerase reverse transcriptase (hTERT) confer cancer cells sustained proliferation and survival potentials. Targeting telomerase or hTERT is a novel anti-cancer strategy. However, telomerase/hTERT inhibition alone has minimal clinical efficacy. We explored the relationship between hTERT and cyclooxygenase 2 (COX2) and evaluated synergistic anti-cancer effects of targeting both hTERT and COX2. Methods: hTERT was depleted in gastric and cervical cancer cells using small interfering RNA (siRNA) and analysed for COX2 expression using quantitative PCR and immunoblotting. Viable cells and apoptotic cells in gastric cancer cells treated with hTERT siRNA or/and the COX2 inhibitor celecoxib were measured using Trypen blue exclusion and flow cytometry. The in vivo anti-cancer effect of hTERT depletion or/and celecoxib was evaluated using mouse xenograft models. Results: Knocking down hTERT expression in cancer cells led to robust increases in mRNA and protein levels of COX2. The COX2 promoter activity increased substantially in hTERT-depleted cells. hTERT depletion led to the activation of p38 mitogen-activated protein kinase responsible for the stimulation of COX2 gene transcription. hTERT depletion or celecoxib alone did not affect cancer cell survival, whereas their combination synergistically killed them both in vitro and in vivo. Conclusion: hTERT induces COX2 expression and simultaneously targeting hTERT and COX2 synergistically kills cancer cells.
    British Journal of Cancer 05/2013; 108(11). DOI:10.1038/bjc.2013.208 · 4.84 Impact Factor
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    • "and angiogenesis (Chen et al., 2009; Liu et al., 2011), inhibiting apoptosis and immune surveillance (Ohno et al., 2005), and enhancing drug resistance (Mehar et al., 2008). These findings suggest that COX-2 may play a key role in carcinogenesis and makes it a potential target in cancer therapy (Ghosh et al., 2010; Khan et al., 2011). "
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    ABSTRACT: Objective: This investigation aimed to determine effects of celecoxib on the cell cycle kinetics of the gastric cancer cell line MGC803 and the mechanisms involved by assessing expression of cytochrome C and caspase-9 at the protein level. Methods: Cell proliferation of MGC803 was determined by MTT assay after treatment with celecoxib. Apoptosis was assessed using fluorescence staining and cell cycle kinetics by flow cytometry. Western blotting was used to detect the expression of caspase-9 protein and of cytochrome C protein in cell cytosol and mitochondria. Results: Celecoxib was able to restrain proliferation and induce apoptosis in a dose- and time- dependent manner, inducing G0/G1 cell cycle arrest, release of cytochrome C into the cytosol, and cleavage of pro-caspase-9 into its active form. Conclusion: Celecoxib can induce apoptosis in MGC803 cells through a mechanism involving cell cycle arrest, mitochondrial cytochrome C release and caspase activation.
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