COX2 expression in neuroblastoma increases tumorigenicity but does not affect cell death in response to the COX2 inhibitor celecoxib

Bell, Emma; Ponthan, Frida; Whitworth, Claire; Tweddle, Deborah A.; Lunec, John; Redfern, Christopher P.F.

doi:10.1007/s10585-014-9656-3

Cited by 6 publications

(4 citation statements)

References 24 publications

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“…Co-treatment with J-4 and Celecoxib in A375 and B16 cells did not significantly affect cell proliferation, but severely impaired cell migration, invasion and adhesion which were all required for melanoma cells motility. The results are consistent with the phenotype induced by PKCζ or COX-2 inhibition in previous reports [ 19 , 35 ], which means cell motility inhibition but not cell death [ 44 ]. The CI value is a widely accepted indicator of synergistic effect [ 39 ].…”

Section: Discussionsupporting

confidence: 93%

Combination therapy of PKCζ and COX-2 inhibitors synergistically suppress melanoma metastasis

Zhou

Qin

et al. 2017

J Exp Clin Cancer Res

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BackgroundMetastatic malignant melanoma is one of the most aggressive malignancies and its treatment remains challenging. Recent studies demonstrate that the melanoma metastasis has correlations with the heightened activations of protein kinase C ζ (PKCζ) and cyclooxygenase-2 (COX-2) signaling pathways. Targeted inhibitions for PKCζ and COX-2 have been considered as the promising strategies for the treatment of melanoma metastasis. Thus, the PKCζ inhibitor J-4 and COX-2 inhibitor Celecoxib were combined to treat melanoma metastasis in this study.MethodsThe Transwell assay, Wound-healing assay and Adhesion assay were used to evaluate the inhibition of combined therapy of J-4 and Celecoxib on melanoma cells invasion, migration and adhesion in vitro, respectively. The impaired actin polymerization was observed by confocal microscope and inactivated signal pathways about PKCζ and COX-2 were confirmed by the Western blotting assay. The B16-F10/C57BL mouse melanoma model was used to test the inhibition of combined therapy of J-4 and Celecoxib on melanoma metastasis in vivo.ResultsThe in vitro results showed that the combination of J-4 and Celecoxib exerted synergistic inhibitory effects on the migration, invasion and adhesion of melanoma B16-F10 and A375 cells with combination index less than 1. The actin polymerization and phosphorylation of Cofilin required in cell migration were severely impaired, which is due to the inactivation of PKCζ related signal pathways and the decrease of COX-2. The combined inhibition of PKCζ and COX-2 induced Mesenchymal-Epithelial Transition (MET) in melanoma cells with the expression of E-Cadherin increasing and Vimentin decreasing. The secretion of MMP-2/MMP-9 also significantly decreased after the combination treatment. In C57BL/6 mice intravenously injected with B16-F10 cells (5 × 104 cells/mouse), co-treatment of J-4 and Celecoxib also severely suppressed melanoma lung metastasis. The body weight monitoring and HE staining results indicated the low toxicity of the combination therapy.ConclusionsThis study demonstrates that the combination therapy of PKCζ and COX-2 inhibitors can significantly inhibit melanoma metastasis in vitro and in vivo, which will be an efficient strategy for treatment of melanoma metastasis in clinics.

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Section: Discussionsupporting

confidence: 93%

Combination therapy of PKCζ and COX-2 inhibitors synergistically suppress melanoma metastasis

Zhou

Qin

et al. 2017

J Exp Clin Cancer Res

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“…Only high concentrations of celecoxib and rofecoxib affected the cell viability, but this did not seem to be a result of COX-2 dependent actions. Interestingly, this phenomenon was also observed in another human melanoma cell line (Mel-Juso), with rarely detectable COX-2 expression [ 38 ], and in human neuroblastoma cell line SH-SY5Y [ 21 ]. For celecoxib, several alternative mechanisms have been described, including inhibition of protein-dependent kinase (PDK) [ 46 , 47 ], carbonic anhydrase [ 27 ] and 5-lipoxygenase [ 48 ].…”

Section: Discussionmentioning

confidence: 76%

“…The question remains as to whether the effects of selective COX-2 inhibitors occur in a COX-2 expression-dependent or independent manner in tumor cells [ 21 , 22 , 23 , 24 , 25 , 26 ]. For example, many reports indicate that the COX-2 selective inhibitor celecoxib does not require the presence of COX-2 to implement its anti-tumor effects [ 22 , 25 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

CRISPR/Cas9 Mediated Knockout of Cyclooxygenase-2 Gene Inhibits Invasiveness in A2058 Melanoma Cells

Haase-Kohn

Laube

Donat

et al. 2022

Cells

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The inducible isoenzyme cyclooxygenase-2 (COX-2) is an important hub in cellular signaling, which contributes to tumor progression by modulating and enhancing a pro-inflammatory tumor microenvironment, tumor growth, apoptosis resistance, angiogenesis and metastasis. In order to understand the role of COX-2 expression in melanoma, we investigated the functional knockout effect of COX-2 in A2058 human melanoma cells. COX-2 knockout was validated by Western blot and flow cytometry analysis. When comparing COX-2 knockout cells to controls, we observed significantly reduced invasion, colony and spheroid formation potential in cell monolayers and three-dimensional models in vitro, and significantly reduced tumor development in xenograft mouse models in vivo. Moreover, COX-2 knockout alters the metabolic activity of cells under normoxia and experimental hypoxia as demonstrated by using the radiotracers [18F]FDG and [18F]FMISO. Finally, a pilot protein array analysis in COX-2 knockout cells verified significantly altered downstream signaling pathways that can be linked to cellular and molecular mechanisms of cancer metastasis closely related to the enzyme. Given the complexity of the signaling pathways and the multifaceted role of COX-2, targeted suppression of COX-2 in melanoma cells, in combination with modulation of related signaling pathways, appears to be a promising therapeutic approach.

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“…Chronic COX-2 overexpression and function associated with inflammation can also lead to the development of malignant lesions . COX-2 overexpression promotes tumorigenicity, angiogenesis, metastasis, and resistance to apoptosis in a wide range of different tumor types, including brain, breast, pancreatic, leukocytic, and, perhaps most prevalently, colorectal cancers. − Thus, activation of COX-2 and COX-2-mediated downstream signaling pathways play a critical role in disease progression of colorectal cancer. Subepithelial stromal cells (especially fibroblasts) of the colon appear to be the primary source of COX-2 in early to premalignant stages of colorectal carcinogenesis .…”

Section: Introductionmentioning

confidence: 99%

Radiosynthesis and Biological Evaluation of [¹⁸F]Triacoxib: A New Radiotracer for PET Imaging of COX-2

et al. 2019

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Inducible isozyme cyclooxygenase-2 (COX-2) is upregulated under acute and chronic inflammatory conditions, including cancer, wherein it promotes angiogenesis, tissue invasion, and resistance to apoptosis. Due to its high expression in various cancers, COX-2 has become an important biomarker for molecular imaging and therapy of cancer. Recently, our group applied in situ click chemistry for the identification of the highly potent and selective COX-2 inhibitor triacoxib. In this study, we present the radiosynthesis in vitro and in vivo radiopharmacological validation of [18F]triacoxib, a novel radiotracer for PET imaging of COX-2. Radiosynthesis of [18F]triacoxib was accomplished using copper-mediated late-stage radiofluorination chemistry. The radiosynthesis, including radio-HPLC purification, of [18F]triacoxib was accomplished within 90 min in decay-corrected radiochemical yields of 72% (n = 7) at molar activities exceeding 90 GBq/μmol. Cellular uptake and inhibition studies with [18F]triacoxib were carried out in COX-2 expressing HCA-7 cells. Cellular uptake of [18F]triacoxib in HCA-7 cells reached 25% radioactivity/mg protein after 60 min. Cellular uptake was reduced by 63% upon pretreatment with 0.1 mM celecoxib, and 90% of the radiotracer remained intact in vivo after 60 min p.i. in mice. [18F]Triacoxib was further evaluated in HCA-7 tumor-bearing mice using dynamic PET imaging, radiometabolite analysis, autoradiography, and immunohistochemistry. PET imaging revealed a favorable baseline radiotracer uptake in HCA-7 tumors (SUV60min = 0.76 ± 0.02 (n = 4)), which could be blocked by 20% through i.p. pretreatment with 2 mg of celecoxib. Autoradiography and immunohistochemistry experiments further the confirmed blocking of COX-2 in vivo. [18F]Triacoxib, whose nonradioactive analogue was identified through in situ click chemistry, is a novel radiotracer for PET imaging of COX-2 in cancer. Despite a substantial amount of nonspecific uptake in vivo, [18F]triacoxib displayed specific binding to COX-2 in vivo and reinforced the feasibility of optimal structure selection by in situ click chemistry. It remains to be elucidated how this novel radiotracer would perform in first-in-human studies to detect COX-2 with PET.

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COX2 expression in neuroblastoma increases tumorigenicity but does not affect cell death in response to the COX2 inhibitor celecoxib

Cited by 6 publications

References 24 publications

Combination therapy of PKCζ and COX-2 inhibitors synergistically suppress melanoma metastasis

Combination therapy of PKCζ and COX-2 inhibitors synergistically suppress melanoma metastasis

CRISPR/Cas9 Mediated Knockout of Cyclooxygenase-2 Gene Inhibits Invasiveness in A2058 Melanoma Cells

Radiosynthesis and Biological Evaluation of [¹⁸F]Triacoxib: A New Radiotracer for PET Imaging of COX-2

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COX2 expression in neuroblastoma increases tumorigenicity but does not affect cell death in response to the COX2 inhibitor celecoxib

Cited by 6 publications

References 24 publications

Combination therapy of PKCζ and COX-2 inhibitors synergistically suppress melanoma metastasis

Combination therapy of PKCζ and COX-2 inhibitors synergistically suppress melanoma metastasis

CRISPR/Cas9 Mediated Knockout of Cyclooxygenase-2 Gene Inhibits Invasiveness in A2058 Melanoma Cells

Radiosynthesis and Biological Evaluation of [18F]Triacoxib: A New Radiotracer for PET Imaging of COX-2

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Product

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Radiosynthesis and Biological Evaluation of [¹⁸F]Triacoxib: A New Radiotracer for PET Imaging of COX-2