Radiosensitizing potential of the selective cyclooygenase-2 (COX-2) inhibitor meloxicam on human glioma cells

Bijnsdorp, Irene V.; Berg, Jaap van den; Kuipers, Gitta K.; Wedekind, Laurine E.; Slotman, Ben J.; Rijn, J. van; Lafleur, M.V.M.; Sminia, Peter

doi:10.1007/s11060-007-9385-4

Cited by 28 publications

(34 citation statements)

References 37 publications

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“…In this study, meloxicam was not observed to have a radiosensitizing effect. it is unclear whether the discrepancy between the results of the study by Bijnsdorp et al (18) and the present study is due solely to the difference in cell lines used. In vivo, the suppression of angiogenesis may be expected as a result of COX-2 inhibition, possibly leading to the potentiation of antitumor effects.…”

Section: Discussioncontrasting

confidence: 81%

“…Several COX-2 inhibitors have been investigated for their radiosensitizing and chemosensitizing activities, as COX-2 inhibition leads to the decreased production of prostaglandins, which are involved in tumor resistance to radiation and chemotherapy (18,19,30,31). In the present study, the combined effect of meloxicam and radiation or 5-FU was observed.…”

Section: Discussionmentioning

confidence: 99%

“…if the effect of meloxicam alone is weak, it may be possible to combine the drug with other chemotherapeutic agents and/or radiation therapy. Under certain experimental conditions, meloxicam has been reported to have radiosensitizing properties (18,19).…”

Section: Introductionmentioning

confidence: 99%

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Antitumor effects of a cyclooxygenase-2 inhibitor, meloxicam, alone and in combination with radiation and/or 5-fluorouracil in cultured tumor cells

Ayakawa¹

2009

Mol Med Rep

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Abstract.To ascertain whether meloxicam used in a clinical setting as a non-steroidal anti-inflammatory drug (NSAID) warrants preclinical in vivo evaluation as an anticancer agent, we investigated its antitumor effects alone and in combination with radiation and/or 5-fluorouracil (5-FU) in cultured cells. Seven cell lines were examined for cyclooxygenase-2 (COX-2) protein expression by immunoblot analysis, and the HelaS3, SccVii and eMT6 cell lines were selected, expressing relatively high, intermediate, and relatively low COX-2 levels, respectively. Antitumor effects were examined using a colony assay. Among the three cell lines, the effect of meloxicam alone was strongest in SccVii cells. With 24 h of drug exposure, meloxicam at concentrations of 250 and 1250 µM had a definite antitumor effect, dependent on the drug exposure time. The effect of meloxicam in combination with radiation and/or 5-FU was also investigated in the SccVii cells. at a meloxicam concentration of 250 µM, the antitumor effect in combination with radiation or 5-FU was increased compared to the effect of radiation or 5-FU alone; however, the combined effect appeared to be additive. at lower concentrations, meloxicam had no radiosensitizing effect, nor did it enhance the effect of 5-FU. A meloxicam concentration of 250 µM is considerably higher than concentrations obtained in humans taking meloxicam as an nSaid. in conclusion, the antitumor effect of meloxicam was not correlated with the level of COX-2 protein expression. The effect of meloxicam in combination with radiation and/or 5-FU appeared to be additive. To evaluate the possibility of using meloxicam as an anticancer agent, in vivo investigations at clinically relevant drug dose levels are required.

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Section: Discussioncontrasting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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Antitumor effects of a cyclooxygenase-2 inhibitor, meloxicam, alone and in combination with radiation and/or 5-fluorouracil in cultured tumor cells

Ayakawa¹

2009

Mol Med Rep

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“…COX-2 plays important roles in tumor growth, metastasis, angiogenesis, and resistance to chemo-and radio-therapy (Shono et al, 2001;Karim et al, 2005;Bijnsdorp et al, 2007;Kang et al, 2007) and has been reported to be aberrantly overexpressed in human glioma (Joki et al, 2000;Prayson et al, 2002;Sminia et al, 2005;Buccoliero et al, 2006). Moreover, increased COX-2 expression is an independent-negative prognostic factor in malignant gliomas (Shono et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Epidermal growth factor-dependent cyclooxygenase-2 induction in gliomas requires protein kinase C-δ

Chang

Gao

et al. 2009

Oncogene

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Earlier, we showed that epidermal growth factor receptor (EGFR) signaling in human glioma cells increased cyclooxygenase-2 (COX-2) expression through p38-mitogen-activated protein kinase (MAPK)-dependent activation of the Sp family of transcription factors. Further mechanistic details of EGFR-dependent induction of COX-2 expression in glioma cells remained elusive. Protein kinase Cs (PKCs) comprise a family of serine-threonine kinases that are major mediators of signaling from receptor tyrosine kinases. Here, we report that PKC-d, a novel PKC isoform, plays a role in EGF-dependent COX-2 induction in human glioma cells. Pharmacological inhibition and genetic silencing (through siRNA or dominantnegative expression) of PKC-d confirm a role for this PKC isoform in EGF-dependent COX-2 induction. Overexpression of a functional PKC-d enhanced COX-2 expression indicating that PKC-d is not only necessary but also sufficient to regulate COX-2 levels. Inhibition of p38-MAPK pharmacologically or with siRNA further shows that p38-MAPK is required for activation of PKC-d by EGF while inhibition of PKC-d had no discernible effects on p38-MAPK activation. Finally, EGF stimulation promotes physical interactions between PKC-d and Sp1 resulting in phosphorylation and nuclear localization of this transcription factor. These data provide the first evidence that PKC-d is a critical link between p38-MAPK and Sp1-dependent COX-2 expression in human glioma cells.

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“…COX-2 levels are frequently elevated in high-grade gliomas. This expression has been associated with their aggressive growth characteristics and poor prognosis for patients (34,35). Selective inhibition of COX-2 by NS-398 (a selective COX-2 inhibitor) in human gliomas in two different in vitro models reduces growth activity (36,37).…”

Section: Discussionmentioning

confidence: 99%

SNS-032 prevents hypoxia-mediated glioblastoma cell invasion by inhibiting hypoxia inducible factor-1α expression

Saha¹

2009

Int J Oncol

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Abstract. Hypoxia and hypoxia inducible factor-1· (HIF-1·) play a critical role in glioblastoma (GBM) which is characterized by highly aggressive and widespread cell invasion into adjacent normal brain tissue. The purpose of this study was to investigate the effect of the novel aminothiazole compound SNS-032 in glioblastoma cell invasion under hypoxic condition. SNS-032 is a potent and selective inhibitor of cyclin-dependent kinases 2, 7 and 9 and inhibits both cell cycle and transcription. We analyzed the effect of SNS-032 (0.5 μM) on HIF-1· expression and its major trans-regulating factors including COX-2, VEGF, MMP-2 and uPAR that are involved in cellular invasion in tumor hypoxia. Our observations demonstrate SNS-032: i) inhibited hypoxia-induced U87MG cell invasion and among all the other inhibitors tested, SNS-032 is the most effective, ii) blocked HIF-1· mediated transcription of COX-2, MMP-2, VEGF and uPAR expression in U87MG cells in response to hypoxia, iii) blocked HIF-1· expression by a proteasome independent pathway. The effects were similar to those observed with HIF-1· siRNA which prevented cellular invasion by blocking HIF-1· expression and its downstream effectors. Taken together, our data suggest that SNS-032 prevents hypoxia-mediated U87MG cell invasion by blocking the expression of HIF-1· and its trans-regulating factors. Our results present an opportunity in controlling highly invasive tumors such as glioblastoma using this novel class of compounds.

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Radiosensitizing potential of the selective cyclooygenase-2 (COX-2) inhibitor meloxicam on human glioma cells

Cited by 28 publications

References 37 publications

Antitumor effects of a cyclooxygenase-2 inhibitor, meloxicam, alone and in combination with radiation and/or 5-fluorouracil in cultured tumor cells

Antitumor effects of a cyclooxygenase-2 inhibitor, meloxicam, alone and in combination with radiation and/or 5-fluorouracil in cultured tumor cells

Epidermal growth factor-dependent cyclooxygenase-2 induction in gliomas requires protein kinase C-δ

SNS-032 prevents hypoxia-mediated glioblastoma cell invasion by inhibiting hypoxia inducible factor-1α expression

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