Enhancement of the Sensitivity of Renal Cell Carcinoma Cells to Fas-Mediated Cytotoxicity and Apoptosis by the Selective Cyclooxygenase-2 Inhibitor JTE-522

Sato, Nodoka; Mizutani, Yoichi; Li, Yong Nan; Fujiwara, Junichi; Ishida, Hirokazu; Toiyama, Daisuke; Abe, Koichi; Hayashi, Issei; Nakanishi, Hiroyuki; Kawauchi, Akihiro; Miki, Tsuneharu

doi:10.1159/000288243

Cited by 7 publications

(6 citation statements)

References 43 publications

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“…Then, we quantified the degree of their capacity of proliferation and invasion, thus confirming that both variables were significantly decreased. This is also in agreement with previous reports 28-30. In addition, our results also showed a dose-dependent suppression in MTT assay as the concentration of meloxicam was increased.…”

Section: Discussionsupporting

confidence: 94%

“…Chen et al28,29 demonstrated not only that the expression of COX-2 was up-regulated in OSRC-2, one of the RCC cell lines but also that the proliferation and progression of OSRC-2 cells were suppressed by anti-sense inhibition of COX-2. Another selective COX-2 inhibitor, JTE-522, also had a cytotoxic effect on RCC cell lines 30. In the current study, by treating two cell lines, Caki-1 and Caki-2, with meloxicam, a selective COX-2 inhibitor, we inhibited COX-2 expression.…”

Section: Discussionmentioning

confidence: 57%

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Cyclooxygenase-2 Expression and Its Prognostic Significance in Clear Cell Renal Cell Carcinoma

et al. 2012

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BackgroundThe prognostic value of cyclooxygenase-2 (COX-2) in human renal cell carcinoma (RCC) remains unclear. The purposes of this study are to elucidate the clinical significance of COX-2 in clear cell RCC (CCRCC) and to assess the treatment effect of COX-2 inhibition on CCRCC cell lines.MethodsUsing tumor samples obtained from 137 patients who had undergone nephrectomy at Seoul National University Hospital, we evaluated COX-2 expression on immunohistochemistry. Moreover, we performed the cell proliferation assay using 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) and cell invasion assay. Thus, we evaluated the effect of meloxicam, an inhibitor of COX-2, in two human CCRCC cell lines.ResultsCancer-specific survival (p=0.038) and progression-free survival (p=0.031) were shorter in the COX-2 high expression group. A multivariate logistic regression model showed that COX-2 expression was an independent risk factor for pTNM stage and Fuhrman nuclear grade. The MTT assay revealed that COX-2 inhibition led to the suppression of the proliferation of CCRCC cell lines. Moreover, it also reduced their invasion capacity.ConclusionsThis study postulates that COX-2 is a poor prognostic indicator in human CCRCC, suggesting that COX-2 inhibition can be a potential therapy in CCRCC.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 57%

Cyclooxygenase-2 Expression and Its Prognostic Significance in Clear Cell Renal Cell Carcinoma

et al. 2012

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“…COX-2 inhibition has been shown to have antitumour activity in cRCC and is postulated to function via a variety of antitumour and antiangiogenic mechanisms (Chen et al , 2004a and 2004b; Sato et al , 2010). COX-2 expression has also been reported to correlate with cRCC prognosis.…”

Section: Discussionmentioning

confidence: 99%

Cox-2 inhibition enhances the activity of sunitinib in human renal cell carcinoma xenografts

et al. 2013

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Background:Sunitinib (Su), a tyrosine kinase inhibitor of VEGFR, is effective at producing tumour response in clear cell renal cell carcinoma (cRCC), but resistance to therapy is inevitable. As COX-2 is a known mediator of tumour growth, we explored the potential benefit of COX-2 inhibition in combination with VEGFR inhibition in attempts at delaying tumour progression on Su.Methods:COX-2 expression was compared with areas of hypoxia in tumours that progressed on Su vs untreated tumours. Mice bearing human cRCC xenografts were treated with Su and the COX-2 inhibitor, celecoxib, and the effects on tumour growth were assessed. Sequential vs concurrent regimens were compared.Results:COX-2 expression was increased in cRCC xenografts in areas of tumour hypoxia. The combination of Su and celecoxib achieved longer times to tumour progression compared to treatment with either agent alone or to untreated control animals in four models. This effect was seen with concurrent but not with sequential therapy.Conclusion:COX-2 inhibition can extend the effectiveness of VEGFR inhibition. This effect is dependent on the timing of therapy. Clinical trials combining Su and COX-2 inhibitors should be considered as a means delaying time to progression on sunitinib in patients with metastatic cRCC.

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“…NSAIDs and COX-2 inhibitors have been widely studied in colorectal cancer prevention, in animal models, and in the treatment of human patients. The bulk of information suggests that COX-2 inhibitors are beneficial in cancer treatment [19][20][21][22][23] . Most research has focused on specific COX-2 inhibition as it has been shown to be the main isoform upregulated in a large number of cancers other than colorectal tumors.…”

Section: Discussionmentioning

confidence: 99%

Etodolac inhibits interleukin-6 production and improves survival combined with chemotherapy in a colon 26 cachexia model

Shibata

Shimura

Gonda

et al. 2010

Ann. Cancer Res. Therap.

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It has been suggested that inflammatory components, including interleukin (IL)-6 and transforming growth factor (TGF)-, play an important role in the formation of cancer cachexia. Cyclooxygenase (COX)-2 has been reported to suppress tumor progression and to inhibit production of these inflammatory mediators, and, thus, may not only be effective in preventing cachexia, but also beneficial for survival. Etodolac, one of the selective COX-2 inhibitors, was administered to mice bearing cachexigenic clones of colon 26, together with either one of two doses (5 and 10 mg/kg/day) of 5-fluorouracil. Serum concentrations of IL-6 were measured in each treatment group. In the groups treated with 5-fluorouracil alone, survival and tumor growth were significantly improved with 10 mg/kg/day. In the group with etodolac alone, survival improved, however, tumor growth was enhanced. Combination of 5-fluorouracil (5 mg/kg/day) and etodolac improved survival, and the enhancement of tumor growth seen in the etodolac only group, disappeared. By combining 5-fluorouracil (10 mg/kg/day) with etodolac, positive effects on survival and tumor growth were obtained. Serum concentrations of IL-6 were elevated in tumor-bearing mice and were significantly suppressed by treatment with etodolac. In the group with combined treatment, the suppressive effect on IL-6 was synergistic. Our findings suggest that the potential use of COX-2 inhibitors in combination with chemotherapy might be therapeutically advantageous especially in patients with terminal stages of cancer.

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Enhancement of the Sensitivity of Renal Cell Carcinoma Cells to Fas-Mediated Cytotoxicity and Apoptosis by the Selective Cyclooxygenase-2 Inhibitor JTE-522

Cited by 7 publications

References 43 publications

Cyclooxygenase-2 Expression and Its Prognostic Significance in Clear Cell Renal Cell Carcinoma

Cyclooxygenase-2 Expression and Its Prognostic Significance in Clear Cell Renal Cell Carcinoma

Cox-2 inhibition enhances the activity of sunitinib in human renal cell carcinoma xenografts

Etodolac inhibits interleukin-6 production and improves survival combined with chemotherapy in a colon 26 cachexia model

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