Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2.

Sheng, Hongmiao; Shao, Jinyi; Kirkland, Susan C.; Isakson, Peter C.; Coffey, Robert J.; Morrow, Jason D.; Beauchamp, R. Daniel; DuBois, Raymond N.

doi:10.1172/jci119400

Cited by 666 publications

(457 citation statements)

References 32 publications

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“…Celecoxib was obtained from Pfizer; MTT [3-(4,5- Cell Culture K562 cells were cultured in RPMI medium, supplemented with 10% FBS, 100 U/mL penicillin, 100 lg/mL streptomycin, and 3.0 Â 10 5 cells were added to each well on a 24-well plate, in triplicate. Celecoxib was diluted with DMSO (Sigma) in a 2-fold dilution series (10,20,40,80, and 160 lM). An equal volume of DMSO was added to control wells.…”

Section: Materials and Methods Materialsmentioning

confidence: 99%

“…Briefly, 200 lL (6 Â 10 4 cells) of a K562 cell suspension were plated in each well of a 96-well plate. After 12 hr, the cells were treated with varying concentrations of celecoxib (10,20,40,80, and 160 lM). An equal volume of DMSO was added to the control well, and the cells were cultured an additional 32 hr; then 20 lL MTT (5 mg/mL) in growth medium was added per well, and the plates incubated at 378C for 4 hr.…”

Section: Cell Proliferation Assaymentioning

confidence: 99%

“…Although several mechanisms are proposed to explain the antitumor action of Cox-2 inhibitors in epithelial cancer cell lines, their effects on apoptotic signaling and cell proliferation have been gaining attention [20,21]. The central component of a cell's apoptotic machinery is a proteolytic system that involves a family of proteases called caspases.…”

Section: Introductionmentioning

confidence: 99%

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Antitumor effects of celecoxib on K562 leukemia cells are mediated by cell‐cycle arrest, caspase‐3 activation, and downregulation of Cox‐2 expression and are synergistic with hydroxyurea or imatinib

et al. 2006

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Celecoxib, a specific cyclooxygenase-2 (Cox-2) inhibitor, has been shown to possess antitumor activity in a variety of cancer cells. However, the antitumor activity of celecoxib in hematopoietic tumors, especially in chronic myeloid leukemia (CML), has not been well established. This study was designed to investigate the effect of celecoxib on growth and apoptosis in a human CML cell line (K562 cells) or in primary CML cells, and to examine the synergistic actions of celecoxib and hydroxyurea or imatinib on K562 cell proliferation and apoptosis. Celecoxib significantly inhibited the growth of both K562 and primary CML cells and induced apoptosis in a dose-dependent fashion. The IC 50 of celecoxib was 46 mM for inhibition of K562 cell proliferation. The effect of celecoxib on growth inhibition was accompanied by the downregulation of cyclin D 1 and cyclin E and p-Rb expression, the upregulation of P 16 INK4a and P27 KIP expression, and a G 1 -S phase arrest of the cell cycle. The proapoptotic effect of celecoxib was determined to be mediated by caspase-3 activation. When K562 cells were pretreated with DEVD-fmk, a specific inhibitor of caspases, the apoptotic activity of celecoxib was, in part, abrogated. Importantly, we demonstrated for the first time that K562 cells were Cox-2-positive both at the mRNA and protein levels. We noted the following observations: (i) we detected Cox-2 mRNA in K562 cells by reverse transcription-PCR (RT-PCR) and protein expression by western blot analysis; (ii) Cox-2 expression in K562 cells was stimulated by IL-1b, a specific inducing agent of Cox-2 expression; (iii) primary CML cells from CML patient bone marrow also exhibited Cox-2 protein expression. Furthermore, Cox-2 expression was downregulated at higher doses of celecoxib (80-160 mM), suggesting a Cox-2-dependent mechanism was involved in the drug's effects of growth inhibition and induction of apoptosis. In addition, a synergistic effect was observed when cells were exposed to low-dose celecoxib (40 mM) and hydroxyurea (10 mM) or a combination of celecoxib (40 mM) and imatinib (0.2 mM). These findings provide the basis for uncovering the mechanism of celecoxib's antitumor effects and developing a new therapeutic strategy for treating CML. Am. J. Hematol. 81:242-255, 2006. V V C 2006 Wiley-Liss, Inc.

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Section: Materials and Methods Materialsmentioning

confidence: 99%

Section: Cell Proliferation Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antitumor effects of celecoxib on K562 leukemia cells are mediated by cell‐cycle arrest, caspase‐3 activation, and downregulation of Cox‐2 expression and are synergistic with hydroxyurea or imatinib

et al. 2006

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“…Numerous studies have shown that the expression of COX-2, one of the two isoforms of COX, is increased significantly in colonic neoplasms compared with normal colonic mucosa, and that COX-2 plays an integral role in colon cancer tumorigenesis and proliferation (Sheng et al, 1997;Sawaoka et al, 1998;Tsujii et al, 1998). However, the cellular and molecular mechanisms governing any possible relationship between gastrin and COX during GI tumour growth have not been elucidated.…”

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confidence: 99%

COX-2 selective inhibition reverses the trophic properties of gastrin in colorectal cancer

et al. 2002

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Gastrin is a gastrointestinal peptide that possesses potent trophic properties on both normal and neoplastic cells of gastrointestinal origin. Previous studies have indicated that chronic hypergastrinaemia increases the risk of colorectal cancer and cancer growth and that interruption of the effects of gastrin could be a potential target in the treatment of colorectal cancer. Here we demonstrate that gastrin leads to a dose-dependent increase in colon cancer cell proliferation and tumour growth in vitro and in vivo, and that this increment is progressively reversed by pretreatment with the cyclo-oxygenase-2 inhibitor NS-398. Gastrin was able to induce cyclo-oxygenase-2 protein expression, as well as the synthesis of prostaglandin E 2 , the major product of cyclo-oxygenase. Moreover, gastrin leads to approximately a two-fold induction of cyclo-oxygenase-2 promoter activity in transiently transfected cells. The results of these studies demonstrate that cyclo-oxygenase-2 appears to represent one of the downstream targets of gastrin and that selective cyclo-oxygenase-2 inhibition is capable of reversing the trophic properties of gastrin and presumably might prevent the growth of colorectal cancer induced by hypergastrinaemia.

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“…Pharmacologic inhibitors of EP4 suppress polyposis in the Apc min model (9), findings consistent with numerous other reports that selective cox-2 inhibitors inhibit polyp development, while administration of PGE2 accelerates their appearance and progression (8,9). These findings in animal models have been extended to studies in human colorectal cancer cell lines, where many of the downstream events of cox-2 inhibition and PGE2 signaling are more readily dissected (11). Taken together, the findings from preclinical models, cell culture and human clinical investigational studies provide a substantial foundation for exploring cox-2 dependent pathways and their intersection with other dominant genetic pathways for growth regulation in chemoprevention of CRC.…”

Section: Cyclooxygenases Aspirin and The Genetics Of Crc Chemoprevenmentioning

confidence: 85%

Translational approaches to addressing complex genetic pathways in colorectal cancer

Early

Fontana

Davidson

2008

Translational Research

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Colorectal cancer (CRC) is among the most prevalent cancers worldwide and represents a major public health challenge in the developed world. From the perspective of translational investigation, scientists have enormous opportunity to elucidate the molecular genetic mechanisms contributing to CRC pathogenesis since the majority of cancers arise from adenomatous precursor lesions. The process of adenoma growth and transformation is accompanied by cumulative mutations in dominant genetic pathways that confer a growth advantage. While this developmental process permits interrogation of informative pathways prior to the development of cancer, only a minority of adenomas progress to CRC. Accordingly, a major challenge for clinical translational investigators is to identify the molecular signatures that indicate increased likelihood for adenoma progression. By corollary, these molecular signatures include mutations in high penetrance alleles, including the Adenomatous Polyposis Coli (APC) gene as well as other alleles in the Wnt/β-catenin signaling pathway that specify increased genetic susceptibility to CRC. Interactions between these high penetrance alleles and other modifier genes as well as with environmental factors are of particular importance in understanding the complex network of events leading to CRC. This brief review will highlight three areas where important questions concerning genetic and environmental risk factors have fueled translational investigation into possible pathways leading to CRC.There have been substantial advances in the last two decades in our understanding of the molecular pathways that lead to colorectal cancer (CRC), the results of research that demonstrated the role of mutational activation of oncogenes coupled with loss of function of tumor suppressor genes in a model that advanced the concept of finite, but cumulative mutational events (summarized in (1)). These studies in preclinical, animal models as well as cell-based models, clinical observational and randomized studies in humans have led to a more complete understanding of the role of both environmental and genetic factors in CRC pathogenesis.One tangible result of this expanded scientific foundation is an emerging consensus that familial or inherited factors play an increasingly relevant role in our approach to patients with CRC(2). Examples of dominant genetic pathways include those governed by Adenomatous Polyposis Coli (APC) tumor suppressor gene, and also the microsatellite instability pathway 4 To whom communication should be directed

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Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2.

Abstract: Abstract

Cited by 666 publications

References 32 publications

Antitumor effects of celecoxib on K562 leukemia cells are mediated by cell‐cycle arrest, caspase‐3 activation, and downregulation of Cox‐2 expression and are synergistic with hydroxyurea or imatinib

Antitumor effects of celecoxib on K562 leukemia cells are mediated by cell‐cycle arrest, caspase‐3 activation, and downregulation of Cox‐2 expression and are synergistic with hydroxyurea or imatinib

COX-2 selective inhibition reverses the trophic properties of gastrin in colorectal cancer

Translational approaches to addressing complex genetic pathways in colorectal cancer

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