These findings suggest that COX-2, functions as a key cancer promoting factor by triggering a positive-feedback loop between macrophages and cancer cells, which could be exploited for breast cancer prevention and therapy.
Among them, compound A33 displayed the most potency against cancer cell lines (IC<sub>50</sub> = 6.43-10.97 μM for F10, HeLa, A549 and MCF-7 cells), lower toxicity to non-cancer cells than celecoxib (A33: IC<sub>50</sub> = 194.01 μM vs.celecoxib: IC<sub>50</sub> = 97.87 μM for 293T cells), and excellent inhibitory activities on COX-2 (IC<sub>50</sub> = 0.17 μM) and 5-LOX (IC<sub>50</sub> = 0.68 μM).
Inhibition of COX-2 by nonsteroidal antiinflammatory drugs reduces the risk of cancer development in humans and suppresses tumor growth in animal models.
The use of specific COX-2 inhibitors in cancer prevention has been associated with higher risk of acute coronary syndrome (ACS) and myocardial infarction.
These findings identify the first reported target and function of human VRK2 as an active kinase playing a role in regulation of cancer cell invasion through the NFAT pathway and COX-2 expression.
We herein investigated whether COX-2 is overexpressed in human airway cancer cell lines, including A549 (lung), Hep-2 (bronchial), and NCI-H292 (alveolar).
Our data demonstrated that IL-1alpha and COX-2 mRNA were frequently co-expressed in human gastric cancer tissues, and suggested that the IL-1alpha-COX-2 pathway might be involved in tumor progression by regulating cancer cell proliferation.
The molecular mechanism(s) by which chronic inflammation drives cancer initiation and promotion include increased production of pro-inflammatory mediators, such as cytokines, chemokines, reactive oxygen intermediates, increased expression of oncogenes, COX-2 (cyclo-oxygenase-2), 5-LOX (5-lipoxygenase) and MMPs (matrix metalloproteinases), and pro-inflammatory transcription factors such as NF-κB (nuclear factor κB), STAT3 (signal transducer and activator of transcription 3), AP-1 (activator protein 1) and HIF-1α (hypoxia-inducible factor 1α) that mediate tumour cell proliferation, transformation, metastasis, survival, invasion, angiogenesis, chemoresistance and radioresistance.
We reported previously that human fibroblasts release 5-methoxytryptophan (5-MTP) which inhibits cancer cell COX-2 overexpression and suppresses cancer cell migration and metastasis.
The results of this study indicate that the new derivatives of OAO and particularly their conjugates with ASP, downregulate the expression of COX-2 in HepG2 cells by modulating the NF-κB signaling pathway and suggest their potential application in the prevention of liver inflammation and cancer.
Evidence includes a direct relationship between COX-2 expression and cancer incidence in humans and animal models, increased tumorigenesis after genetic manipulation of COX-2, and significant anti-tumor properties of non-steroidal anti-inflammatory drugs in animal models and in some human cancers.