@article{44bab3c434fb461d99beb3bbe574d1c3,
title = "Dimethyl-celecoxib (DMC), a derivative of celecoxib that lacks cyclooxygenase-2-inhibitory function, potently mimics the anti-tumor effects of celecoxib on Burkitt's lymphoma in vitro and in vivo",
abstract = "The nonsteroidal anti-inflammatory drug (NSAID) celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor that has shown some promising results as an anti-cancer drug. However, the question arose as to whether or not its COX-2-inhibitory function is required for its anti-tumorigenic properties. We therefore employed dimethyl-celecoxib (DMC), which is a close structural analog of celecoxib that lacks COX-2-inhibitory function, to investigate this question. By performing a combination of in vitro and in vivo studies with Burkitt's lymphoma cells, we found that DMC potently mimics all of the anti-proliferative and anti-tumorigenic effects of celecoxib. In cell culture, DMC effectively inhibits cell proliferation through the down-regulation of cyclins A and B and the ensuing loss of cyclin-dependent kinase activity. This effect appears to take place in vivo as well and results in significantly (p < .002) reduced tumor growth in experimental animals. Thus, our results demonstrate that the anti-proliferative and anti-tumorigenic properties of celecoxib and DMC are indistinguishable, at least in Burkitt's lymphoma cells, and therefore, that the COX-2-inhibitory function is not required for these effects.",
keywords = "Bextra, Burkitt's lymphoma, CDK, Celebrex, Celecoxib, Cell cycle, Cyclins, DMC, Flurbiprofen, Indomethacin, Lymphoma, NSAIDs, Raji, Ramos, Rofecoxib, Sulindac, Valdecoxib, Vioxx",
author = "Adel Kardosh and Weijun Wang and Jasim Uddin and Petasis, {Nicos A.} and Hofman, {Florence M.} and Chen, {Thomas C.} and Sch{\"o}nthal, {Axel H.}",
note = "Funding Information: State University, Columbus, OH) for providing a Celecoxib is widely prescribed under the trade name Celebrex{\textregistered} for relief of symptoms sample of DMC for preliminary experiments, to of osteoarthritis and rheumatoid arthritis, and was recently approved as an adjunct to A6876 cell line, and to Dr. Ross Bremner (USC,Dr. Parkash S. Gill (USC, Los Angeles, CA) for the standard care for patients with familial adenomatous polyposis (FAP). Although not yet Los Angeles, CA) for anti-COX-2 antibodies. We directly demonstrated, it is suspected that celecoxib might be useful for the prevention and are indebted to Jennifer Bain and Professor Sir treatment of colorectal and possibly other types of cancers, and several clinical trials are Philip Cohen at the University of Dundee currently ongoing to confirm this expectation.9,10 In addition, celecoxib has also been (Dundee, Scotland) for performing in vitro kinase shown to act as a potent anti-tumor agent that prevents or greatly reduces the growth of assays with their collection of purified protein different experimental tumors in animals (reviewed in refs. 11 and 12–19). kinases. The technical assistance of Susan Su is Despite these promising results, the underlying molecular mechanism(s) by which acknowledged. Parts of this project was supported celecoxib—and other NSAIDs—exert their anti-tumorigenic property has remained by funding from the James H. Zumberge Faculty controversial. For example, the conclusion that COX-2 is the central switch by which Research & Innovation Fund (to A.H.S., N.A.P. traditional NSAIDs and coxibs exert their anti-neoplastic effect has been challenged by the and T.C.C.). observation that COX inhibitors can achieve anti-proliferative outcomes through COX-independent mechanisms as well.20 For instance, NSAIDs were shown to inhibit the {\textcopyright}2005 LANDES BIOSCIENCE 21-23 proliferation of cancer cells that do not express either COX isoform. Moreover, transformed cell lines derived from knock-out mice, where the genes for either COX-1 or COX-2 or both were deleted, exhibit comparable sensitivity to NSAID-induced growth inhibition and cell death.24 Although several nonCOX cellular targets have been proposed to explain these effects (refs. 25 and 26, and refs. 7, 11 and 27), the precise underlying mechanism of these drugs{\textquoteright} antiproliferative effects has not been established. In addition, it",
year = "2005",
month = may,
doi = "10.4161/cbt.4.5.1699",
language = "English (US)",
volume = "4",
pages = "571--582",
journal = "Cancer Biology and Therapy",
issn = "1538-4047",
publisher = "Landes Bioscience",
number = "5",
}